Anti-apoptotic protein BCL-2 inhibitors, pharmaceutical compositions and uses thereof

Abstract

Disclosed is a BCL-2 protein apoptosis inducer, and further discloses the application of said compound and pharmaceutical composition containing said compound in the manufacture of a medicament for treating diseases associated with the anti-apoptotic protein BCL-2.The compound has a strong BCL-2 / BAK blocking activity and can be used to treat diseases such as infectious diseases, immune diseases, inflammatory diseases, or cell proliferation disorders that benefit from the inhibition of the anti-apoptotic protein BCL-2.

Description

[Technical Field]

[0001] The present invention belongs to the field of pharmaceutical synthesis technology, specifically to anti-apoptotic B-cell lymphoma-2 (BCL-2) inhibitors, pharmaceutical compositions and uses thereof. [Background technology]

[0002] Apoptosis, also known as programmed cell death, is regulated by both the extrinsic and intrinsic pathways. Apoptosis is closely related to the onset and progression of many human diseases, and inhibition of apoptosis is associated with the onset of diseases such as tumors.

[0003] The Bcl-2 family of proteins includes anti-apoptotic proteins such as BCL-2, BCL-XL, and MCL-1, and pro-apoptotic proteins such as Bid, Bim, Bad, Bak, and Bax. Anti-apoptotic Bcl-2 family members are upregulated in several malignant tumors and have been found to correlate with disease stage and prognosis. Therefore, Bcl-2 proteins have been investigated as potential therapeutic targets and have become the focus of anti-tumor drug research in recent years.

[0004] Bcl-2 protein expression is known as an independent marker 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 already been approved by the FDA and is commercially available. Numerous publications and patents, including Nature Medicine (2013), 19(2), 202-210; WO2021208963A / WO2021173523A / WO2020140005A2 / WO2019210828A1, have reported Bcl-2 inhibitors. However, with the use of Bcl-2 inhibitors, some patients develop resistance after treatment with Bcl-2 inhibitors. G101V and D103Y mutations appear in the BCL-2 gene, reducing the therapeutic effect of BCL-2 inhibitors (Cancer Discov. 2019, 9, 342-353). Finding more suitable treatments for patients who are resistant to BCL-2 inhibitors is urgently needed.

[0005] Therefore, there is an urgent need to develop novel Bcl-2 inhibitors that have good therapeutic effects, high stability, superior safety, and are more effective against mutant cell lines. Summary of the Invention

[0006] The object of the present invention is to provide novel, previously unreported pharmaceutical compositions comprising compounds or optical isomers, stereoisomers or mixtures of stereoisomers thereof or pharmaceutically acceptable salts thereof that inhibit anti-apoptotic B-cell lymphoma-2 (Bcl-2) family proteins, and their use in the manufacture of medicaments for the treatment of diseases (e.g., hyperproliferative diseases such as cancer and inflammation, and immune and autoimmune diseases), disorders or conditions that benefit from the inhibition of anti-apoptotic B-cell lymphoma-2 (Bcl-2).

[0007] According to a first aspect of the present invention, there is provided a compound according to formula I, or a stereoisomer thereof, or a mixture of stereoisomers thereof, or a pharmaceutically acceptable salt thereof:

[0008] JPEG0007765790000001.jpg124134

[0009] *The C in the notation is either R or S configuration. Ring A is selected from absent, a 3- to 10-membered cycloalkyl group, a 4- to 10-membered cycloalkenyl group, a 5- to 10-membered cycloalkynyl group, a 4- to 10-membered heterocyclyl group, a 6- to 10-membered aryl ring, and a 5- to 10-membered heteroaryl ring, wherein the heterocyclyl group and the heteroaryl ring contain 1 to 4 heteroatoms selected from N, O, and S; R2 is hydrogen, deuterium, -C1-C8 alkyl group, -C2-C8 alkenyl group, -C2-C8 alkynyl group, -C1-C8 alkoxy group, cycloalkyl group, 4-10 membered heterocyclyl group, aryl group, heteroaryl group, halogen, hydroxy group, amino group, oxo group, cyano group, nitro group, -OR g , -SR g , -S(O)R g , -SO2R 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 , -NR h S(O)NR i R h , -NR h SO2NR i R h , -P(O)R h R i, a halogenated C1-C8 alkyl group, a halogenated C1-C8 alkoxy group, a halogenated C1-C8 cycloalkyl group, a hydroxy-substituted C1-C8 alkyl group, or a hydroxy-substituted C1-C8 alkoxy group, wherein when two R2 are on the same atom they may form a 3- to 6-membered spiro ring, or when they are on adjacent atoms they may form a 3- to 8-membered fused ring;

[0010] Y1, Y2, and Y3 are each independently selected from CR7 and N; R7 is selected from H, halogen (preferably F), C1-C8 alkyl group, halogenated C1-C8 alkyl group, cycloalkyl group, alkoxy group; L2 is a chemical bond, -NR a -, -O-, -S-, -C(O)-, -C(O)NR a -, -NR a C(O)-, L3 is selected from -C(O)NR8SO2-;

[0011] R8 is H, C1-C8 alkyl group, -R P OC(O)R q , -R p OC(O)OR q , -R p OC(O)NR q R s , -R p COOR q is selected from R p , R q , R s are each independently selected from H, a C1-C8 alkyl group, a 3- to 10-membered cycloalkyl group, a 4- to 10-membered heterocyclyl group, an aryl group, and a 5- to 10-membered heteroaryl group, wherein the alkyl group, cycloalkyl group, heterocyclyl group, aryl group, and heteroaryl group are optionally further substituted with a C1-C8 alkyl group, a 3- to 10-membered cycloalkyl group, a 4- to 10-membered heterocyclyl group, an aryl group, or a 5- to 10-membered heteroaryl group;

[0012] R3 is Selected from JPEG0007765790000002.jpg44149,

[0013] R 10 is selected from hydrogen, deuterium, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, halogen, nitro, oxo, cyano, and halogenated alkyl groups; R 10 may be substituted on a carbon atom or a nitrogen atom,

[0014] Ring B is selected from 5-12 membered spiroheterocyclyl groups; Ring C is selected from a cycloalkyl group, a cycloalkenyl group, a bridged cyclic group, a heterocyclyl group, an aryl group, or a heteroaryl group;

[0015] X is CR b R c , N.R. b is selected from o is selected from 0, 1, 2, 3, and 4, p is selected from 0, 1, 2, and 3; q is selected from 0, 1, 2, and 3, r is selected from 0, 1, 2, and 3, s is selected from 0, 1, 2, and 3, t is selected from 0, 1, 2, and 3,

[0016] R a , R b , R c are each independently selected from H, deuterium, halogen, C1-C8 alkyl, alkoxy, cycloalkyl, heterocyclyl, heteroaryl, and aryl groups, and the alkyl, cycloalkyl, heteroaryl, and aryl groups may further comprise one or more R d may be substituted with a substituent,

[0017] R dis selected from H, deuterium, halogen, C1-C8 alkyl, alkoxy, oxo, amino, hydroxy, cyano, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and fused bicyclic groups, and the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, heteroaryl, aryl, and fused bicyclic groups may further comprise one or more R e may be substituted with a substituent, and two R e may form a 3- to 6-membered spiro ring when they are on the same atom, or may form a 3- to 8-membered fused ring when they are on adjacent atoms;

[0018] R e is selected from H, deuterium, halogen, C1-C8 alkyl group, C1-C8 alkoxy group, oxo, amino group, hydroxy group, cyano group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclyl group, haloalkyl group, haloalkoxy group, methylsulfonyl group, aryl group, and heteroaryl group, and the alkyl group, alkoxy group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclyl group, heteroaryl group, and aryl group are each independently selected from the group consisting of one or more R m and two R m may form a 3- to 6-membered spiro ring when they are on the same atom, or may form a 3- to 8-membered fused ring when they are on adjacent atoms;

[0019] R4 is selected from H, halogen, C1-C8 alkyl groups, halogenated C1-C8 alkyl groups, cycloalkyl groups, and alkoxy groups; R5 is selected from H, deuterium, halogen, C1-C8 alkyl groups, haloalkyl groups, alkoxy groups, cycloalkyl groups, heterocyclyl groups, heteroaryl groups, and aryl groups;

[0020] R6 is selected from H, deuterium, halogen, C1-C8 alkyl, haloalkyl, alkoxy, cycloalkyl, heterocyclyl, heteroaryl, and aryl groups; L1 is a chemical bond, NR f, O,

[0021] R f is selected from H, a C1-C8 alkyl group, a haloalkyl group, a cycloalkyl group, a heterocyclyl group, a heteroaryl group, and an aryl group; R1 is hydrogen, deuterium, an alkyl group, a bridged cyclic group, a spirocyclic group, an alkenyl group, an alkynyl group, a cycloalkyl group, a cycloalkenyl group, a heterocyclyl group, an aryl group or a heteroaryl group, a halogen atom, a nitro group, an oxo group, a cyano group, -OR g , -SR g , alkyl group -R g , NH(CH)R g , -C(O)R g , -S(O)R g , -SO2R g , -C(O)OR g , -OC(O)R g , -NR h R i , C(O)N(R h )R i , -N(R h )C(O)R i , -NR h C(O)NR i R h , -NR h C(O)OR g , -NR h S(O)NR i R h , -NR h SO2NR i R h , -P(O)R h R i wherein the alkyl group, bridged cyclic group, spirocyclic group, alkenyl group, alkynyl group, cycloalkyl group, cycloalkenyl group, heterocyclyl group, aryl group or heteroaryl group may further be selected from one or more R j may be substituted with

[0022] R g , R h , R i , R jis selected from hydrogen, deuterium, a C1-C8 alkyl group, a spirocyclic group, an alkenyl group, an alkynyl group, a halogen, a cyano group, an amino group, a nitro group, a hydroxy group, an oxo group, a carboxy group, an amido group, an alkoxy group, a haloalkyl group, a hydroxyalkyl group, an aminoalkyl group, an alkylcarbonyl group, an alkoxycarbonyl group, an alkylamino group, a halohydroxyalkyl group, a haloalkylamino group, a cycloalkyl group, a cycloalkenyl group, a bridged cyclic group, a heterocyclyl group, an aryl group, or a heteroaryl group, and the alkyl group, spirocyclic group, alkenyl group, alkynyl group, alkoxy group, hydroxyalkyl group, aminoalkyl group, alkylcarbonyl group, alkoxycarbonyl group, alkylamino group, cycloalkyl group, cycloalkenyl group, bridged cyclic group, heterocyclyl group, aryl group, or heteroaryl group may further comprise one or more R m may be substituted with

[0023] R m is selected from hydrogen, deuterium, a C1-C8 alkyl group, a halogen, a cyano group, an amino group, a nitro group, a hydroxy group, an oxo group, an alkoxy group, a haloalkyl group, a hydroxyalkyl group, an aminoalkyl group, an alkylcarbonyl group, an alkoxycarbonyl group, an alkylamino group, a halohydroxyalkyl group, a haloalkylamino group, a cycloalkyl group, and a heterocyclyl group, and the alkyl group, cycloalkyl group, and heterocyclyl group may further comprise one or more R r may be substituted with

[0024] R r is selected from hydrogen, deuterium, a C1-C8 alkyl group, a halogen, a cyano group, an amino group, a hydroxy group, an oxo group, an alkoxy group, a hydroxyalkyl group, an aminoalkyl group, an alkylcarbonyl group, a heterocyclyl group, an alkylamino group, an alkoxycarbonyl group, a halohydroxyalkyl group, a haloalkylamino group, a haloalkyl group, a cycloalkyl group, a spirocyclic group, an alkenyl group, an alkynyl group, a nitro group, a carboxy group, an amido group, a cycloalkenyl group, a bridged cyclic group, an aryl group, or a heteroaryl group;

[0025] When ring A is selected from absent: X is NR b and at least one of Y1 / Y2 / Y3 is selected from N or CR7, and R7 is not H. In some embodiments, the ring A is preferably absent or

[0026] JPEG0007765790000003.jpg42170.

[0027] Furthermore, in some embodiments, JPEG0007765790000004.jpg60142 is preferably

[0028] JPEG0007765790000005.jpg126170.

[0029] In some embodiments, the ring B is preferably JPEG0007765790000006.jpg69134.

[0030] In some embodiments, the ring C is preferably an aryl ring or a heteroaryl ring.

[0031] In some embodiments, when ring A is selected from a 4-10 membered heterocyclyl group, a 5-10 membered heteroaryl ring, Y2 is N, CH, or CF; when ring A is selected from absent, Y2 is N or CF; X is NR b and at least one of Y1 / Y2 / Y3 is selected from N or CR7, and R7 is not H.

[0032] Additionally, preferred compounds of the present invention have the structure of general formula I': JPEG0007765790000007.jpg123138 or a stereoisomer thereof or a mixture of stereoisomers thereof or a pharmaceutically acceptable salt thereof, *The C in the notation is either R or S configuration. Ring A does not exist, JPEG0007765790000008.jpg391186-10 membered heterocyclic ring, 6-10 membered aryl ring, 6-10 membered heteroaryl ring, Z is selected from N, CH; R2 is selected from hydrogen, deuterium, a C1-C8 alkyl group, a halogen, and a halogenated C1-C8 alkyl group;

[0033] Y1, Y2, and Y3 are each independently selected from CR7 and N; R7 is selected from H, halogen, C1-C8 alkyl groups, halogenated C1-C8 alkyl groups, cycloalkyl groups, and alkoxy groups; When ring A is selected from absent and two of Y1, Y2, and Y3 are CH, Another one of Y1 / Y2 / Y3 is N or CR7, and R7 is not H; R3 is Selected from JPEG0007765790000009.jpg43150,

[0034] R 10 is selected from hydrogen, deuterium, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, halogen, nitro, oxo, cyano, and halogenated alkyl groups; R 10 may be substituted on a carbon atom or a nitrogen atom,

[0035] Ring B is Selected from JPEG0007765790000010.jpg70142,

[0036] o is selected from 0, 1, 2, 3, and 4, p is selected from 0, 1, 2, and 3; q is selected from 0, 1, 2, and 3, r is selected from 0, 1, 2, and 3, s is selected from 0, 1, 2, and 3, L2 is a chemical bond, NR a , O, X is CR b R c , N.R. b is selected from

[0037] R a , R b , R c are each independently selected from H, deuterium, halogen, C1-C8 alkyl, alkoxy, cycloalkyl, heterocyclyl, heteroaryl, and aryl groups, and the alkyl, cycloalkyl, heteroaryl, and aryl groups may further comprise one or more R d may be substituted with a substituent,

[0038] R d is selected from H, deuterium, halogen, C1-C8 alkyl, alkoxy, oxo, amino, hydroxy, cyano, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and fused bicyclic groups, and the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, heteroaryl, aryl, and fused bicyclic groups may further comprise one or more R e may be substituted with a substituent, and two R e may form a 3- to 6-membered spiro ring when on the same carbon atom, or may form a 3- to 8-membered fused ring when on adjacent carbon atoms;

[0039] R e is selected from H, deuterium, halogen, C1-C8 alkyl group, C1-C8 alkoxy group, oxo, amino group, hydroxy group, cyano group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclyl group, haloalkyl group, haloalkoxy group, and methylsulfonyl group;

[0040] R4 is selected from H, halogen, C1-C8 alkyl groups, halogenated C1-C8 alkyl groups, cycloalkyl groups, and alkoxy groups; R5 is selected from H, deuterium, halogen, C1-C8 alkyl groups, haloalkyl groups, alkoxy groups, cycloalkyl groups, heterocyclyl groups, heteroaryl groups, and aryl groups; R6 is selected from H, deuterium, halogen, C1-C8 alkyl, haloalkyl, alkoxy, cycloalkyl, heterocyclyl, heteroaryl, and aryl groups;

[0041] Ring C is selected from a cycloalkyl group, a cycloalkenyl group, a bridged cyclic group, a heterocyclyl group, an aryl group, or a heteroaryl group; L1 is NR f , O, R f is selected from H, a C1-C8 alkyl group, a haloalkyl group, a cycloalkyl group, a heterocyclyl group, a heteroaryl group, and an aryl group;

[0042] R1 is hydrogen, deuterium, an alkyl group, a bridged cyclic group, a spirocyclic group, an alkenyl group, an alkynyl group, a cycloalkyl group, a cycloalkenyl group, a heterocyclyl group, an aryl group or a heteroaryl group, a halogen atom, a nitro group, an oxo group, a cyano group, an OR group, g , S.R. g , alkyl group -R g , NH(CH)R g , C(O)R g , S(O)R g , SO2R g , C(O)OR g ,OC(O)R g , N.R. h R i , C(O)N(R h )R i , N(R h )C(O)R i , -P(O)R h R i wherein the alkyl group, bridged cyclic group, spirocyclic group, alkenyl group, alkynyl group, cycloalkyl group, cycloalkenyl group, heterocyclyl group, aryl group or heteroaryl group may further be selected from one or more R j may be substituted with

[0043] R g , R h , R i , R j is selected from hydrogen, deuterium, a C1-C8 alkyl group, a spirocyclic group, an alkenyl group, an alkynyl group, a halogen, a cyano group, an amino group, a nitro group, a hydroxy group, an oxo group, a carboxy group, an amido group, an alkoxy group, a haloalkyl group, a hydroxyalkyl group, an aminoalkyl group, an alkylcarbonyl group, an alkoxycarbonyl group, an alkylamino group, a halohydroxyalkyl group, a haloalkylamino group, a cycloalkyl group, a cycloalkenyl group, a bridged cyclic group, a heterocyclyl group, an aryl group, or a heteroaryl group, and the alkyl group, spirocyclic group, alkenyl group, alkynyl group, alkoxy group, hydroxyalkyl group, aminoalkyl group, alkylcarbonyl group, alkoxycarbonyl group, alkylamino group, cycloalkyl group, cycloalkenyl group, bridged cyclic group, heterocyclyl group, aryl group, or heteroaryl group may further comprise one or more R m may be substituted with

[0044] R m is selected from hydrogen, deuterium, a C1-C8 alkyl group, a halogen, a cyano group, an amino group, a nitro group, a hydroxy group, an oxo group, an alkoxy group, a haloalkyl group, a hydroxyalkyl group, an aminoalkyl group, an alkylcarbonyl group, an alkoxycarbonyl group, an alkylamino group, a halohydroxyalkyl group, a haloalkylamino group, a cycloalkyl group, and a heterocyclyl group, and the alkyl group, cycloalkyl group, and heterocyclyl group may further comprise one or more R r may be substituted with

[0045] R ris selected from hydrogen, deuterium, a C1-C8 alkyl group, a halogen, a cyano group, an amino group, a hydroxy group, an oxo group, an alkoxy group, a hydroxyalkyl group, an aminoalkyl group, a heterocyclyl group, an alkylamino group, an alkylcarbonyl group, an alkoxycarbonyl group, a halohydroxyalkyl group, a haloalkylamino group, a haloalkyl group, a cycloalkyl group, a spirocyclic group, an alkenyl group, an alkynyl group, a nitro group, a carboxy group, an amido group, a cycloalkenyl group, a bridged cyclic group, an aryl group, or a heteroaryl group.

[0046] Furthermore, preferred compounds of the present invention have the structure shown in general formula IIa and IIb: JPEG0007765790000011.jpg111170

[0047] or a stereoisomer thereof, a mixture of stereoisomers thereof, or a pharmaceutically acceptable salt thereof. Furthermore, preferred compounds of the present invention have the structure shown in general formula IIIa and IIIb: JPEG0007765790000012.jpg124170 or a stereoisomer thereof or a mixture of stereoisomers thereof or a pharmaceutically acceptable salt thereof.

[0048] Furthermore, preferred compounds of the present invention have the structure shown in general formula IVa, IVb, IVc: JPEG0007765790000013.jpg72170

[0049] or a stereoisomer thereof, a mixture of stereoisomers thereof, or a pharmaceutically acceptable salt thereof; R2 is selected from hydrogen, deuterium, a C1-C8 alkyl group, halogen, and a halogenated C1-C8 alkyl group, and R2 may be substituted on a carbon atom or a nitrogen atom.

[0050] Furthermore, preferred compounds of the present invention have structures represented by general formulas Va to Vf, JPEG0007765790000014.jpg154170

[0051] or a stereoisomer thereof, a mixture of stereoisomers thereof, or a pharmaceutically acceptable salt thereof; R 10 is selected from hydrogen, deuterium, an alkyl group, a cycloalkyl group, a halogen, a nitro group, a cyano group, and a halogenated alkyl group; R2 is selected from hydrogen, deuterium, a C1-C8 alkyl group, halogen, and a halogenated C1-C8 alkyl group, and R2 may be substituted on a carbon atom or a nitrogen atom.

[0052] Furthermore, preferred compounds of the present invention have the structure shown in general formula VIa and VIb: JPEG0007765790000015.jpg104170 or a stereoisomer thereof or a mixture of stereoisomers thereof or a pharmaceutically acceptable salt thereof, When two of Y1, Y2, and Y3 are CH, the other one of Y1 / Y2 / Y3 is N or CR7; R7 is selected from halogen, a C1-C8 alkyl group, a halogenated C1-C8 alkyl group, a cycloalkyl group, and an alkoxy group.

[0053] Furthermore, preferred compounds of the present invention are Ring A is selected from a 4-membered heterocycle, a 5-membered heterocycle, and a 5-membered heteroaryl group; L3 is selected from -C(O)NHSO2-; Ring C is selected from an aryl group or a heteroaryl group, more preferably, Ring C is selected from a benzene ring; Ring B is JPEG0007765790000016.jpg66126, and the nitrogen is attached to the ring containing Y1 / Y2 / Y3.

[0054] Furthermore, in the preferred compounds of the present invention, and stereoisomers thereof, stereoisomeric mixtures thereof, or pharmaceutically acceptable salts thereof, X is CR b R c is selected from R b , R care each independently selected from H, deuterium, halogen, a C1-C8 alkyl group, a C1-C8 alkoxy group, a cycloalkyl group, a heterocyclyl group, a heteroaryl group, and an aryl group; O is selected from 0, 1, and 2, L2 is selected from a chemical bond, -NH-, and -O-; Furthermore, preferred compounds of the present invention have the structure of general formula (VII): JPEG0007765790000017.jpg146170 or a stereoisomer thereof or a mixture of stereoisomers thereof or a pharmaceutically acceptable salt thereof, where: Y1, Y2, and Y3 are each independently selected from CR7 and N; R7 is selected from H, halogen, a C1-C8 alkyl group, a halogenated C1-C8 alkyl group, a cycloalkyl group, and an alkoxy group.

[0055] Ring B is Selected from JPEG0007765790000018.jpg67135.

[0056] In some embodiments, the segments in general formula (I), (I'), II(b), III(b), IV(c), Ve-Vf, VIa-VIb, VII JPEG0007765790000019.jpg79143R b is preferably Selected from JPEG0007765790000020.jpg188170.

[0057] In some embodiments, R1 is JPEG0007765790000021.jpg49125, any carbon atom on the ring is substituted with one or more N or O; y is selected from 0, 1, 2, 3, and 4, v is selected from 0, 1, 2, and 3.

[0058] In some embodiments, the segment -L1-R1 in general formula I, I', IIa-IIb, IIIa-IIIb, IVa-IVc, Va-Vf, VIa, VIb, VII is Selected from JPEG0007765790000022.jpg92170.

[0059] Preferably, the compound or a stereoisomer thereof or a mixture of stereoisomers thereof or a pharmaceutically acceptable salt thereof is selected from the following compounds: 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

[0060] (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

[0061] (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

[0062] (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

[0063] (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

[0064] (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

[0065] 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

[0066] (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

[0067] 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

[0068] (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

[0069] 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

[0070] (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

[0071] 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 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

[0072] (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

[0073] (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

[0074] 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

[0075] 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

[0076] (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

[0077] (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

[0078] (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

[0079] (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

[0080] (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

[0081] (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

[0082] (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

[0083] (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

[0084] (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

[0085] (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

[0086] (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

[0087] (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

[0088] (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

[0089] (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

[0090] 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 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

[0091] 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

[0092] (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

[0093] 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

[0094] (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

[0095] 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

[0096] 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]heptan-2-yl)benzamide 040

[0097] 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

[0098] 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]heptan-2-yl)benzamide 042

[0099] 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

[0100] 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]heptan-2-yl)benzamide 044

[0101] 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

[0102] 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]heptan-2-yl)benzamide 046

[0103] 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

[0104] 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

[0105] 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

[0106] 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

[0107] 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

[0108] 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]heptan-2-yl)nicotinamide 052

[0109] 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

[0110] 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]heptan-2-yl)nicotinamide 054

[0111] 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

[0112] 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]heptan-2-yl)benzamide 056

[0113] 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

[0114] 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]heptan-2-yl)benzamide 058

[0115] 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

[0116] 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

[0117] 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

[0118] 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

[0119] 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

[0120] 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

[0121] 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

[0122] 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

[0123] 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

[0124] 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]heptan-2-yl)nicotinamide 068

[0125] 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

[0126] 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]heptan-2-yl)nicotinamide 070

[0127] 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

[0128] 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]heptan-2-yl)benzamide 072

[0129] 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

[0130] 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

[0131] 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

[0132] 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

[0133] 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

[0134] 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

[0135] 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

[0136] (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

[0137] 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

[0138] 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

[0139] (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

[0140] (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

[0141] 2-(3,4-Dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-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

[0142] (S)-2-(3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-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

[0143] (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

[0144] (S)-2-(3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-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

[0145] 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

[0146] 2-(3,4-Dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-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

[0147] 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

[0148] 2-(3,4-Dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-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

[0149] 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

[0150] 2-(3,4-Dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-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

[0151] 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

[0152] 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]dioxol-4-yl)sulfonyl)-4-(2-((S)-2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide 096

[0153] 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

[0154] 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

[0155] 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

[0156] 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

[0157] (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]dioxol-4-yl)sulfonyl)-4-(2-(2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide 101

[0158] (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

[0159] (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

[0160] (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

[0161] (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

[0162] (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]dioxol-4-yl)sulfonyl)-4-(2-(2-(2-isopropylphenyl)-4-(4-methoxybenzyl)piperazin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide 106

[0163] (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

[0164] (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

[0165] (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

[0166] (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

[0167] (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

[0168] (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

[0169] 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]dioxol-4-yl)sulfonyl)-4-(2-((R)-2-(2-isopropylphenyl)-4-(4-methoxybenzyl)piperazin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide 113

[0170] 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

[0171] 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

[0172] 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

[0173] 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

[0174] 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

[0175] 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

[0176] (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]dioxol-4-yl)sulfonyl)benzamide 120

[0177] (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

[0178] (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

[0179] N-((7-((((S)-1,4-dioxan-2-yl)methyl)amino)-6-nitrobenzo[d][1,3]dioxol-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

[0180] 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

[0181] 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

[0182] (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]dioxol-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

[0183] (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

[0184] (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

[0185] (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

[0186] (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]dioxol-4-yl)sulfonyl)benzamide 130

[0187] (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

[0188] (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]dioxol-4-yl)sulfonyl)-6-(2-(2-(2-isopropylphenyl)-4-(4-methoxybenzyl)piperazin-1-yl)-7-azaspiro[3.5]nonan-7-yl)nicotinamide 132

[0189] (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

[0190] (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

[0191] (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

[0192] (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

[0193] 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]dioxol-4-yl)sulfonyl)-6-(2-((R)-2-(2-isopropylphenyl)-4-(4-methoxybenzyl)piperazin-1-yl)-7-azaspiro[3.5]nonan-7-yl)nicotinamide 137

[0194] 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

[0195] 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

[0196] 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

[0197] (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

[0198] (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

[0199] (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

[0200] (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

[0201] (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]dioxol-4-yl)sulfonyl)benzamide 145

[0202] (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

[0203] (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]dioxol-4-yl)sulfonyl)-4-(2-(2-(2-isopropylphenyl)-4-(4-methoxybenzyl)piperazin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide 147

[0204] N-((7-((((S)-1,4-dioxan-2-yl)methyl)amino)-6-nitrobenzo[d][1,3]dioxol-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

[0205] 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]dioxol-4-yl)sulfonyl)-4-(2-((R)-2-(2-isopropylphenyl)-4-(4-methoxybenzyl)piperazin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide 149

[0206] (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]dioxol-4-yl)sulfonyl)nicotinamide 150

[0207] N-((7-((((S)-1,4-dioxan-2-yl)methyl)amino)-6-nitrobenzo[d][1,3]dioxol-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

[0208] (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

[0209] (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

[0210] 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

[0211] 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

[0212] (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]dioxol-4-yl)sulfonyl)benzamide 156

[0213] N-((7-((((S)-1,4-dioxan-2-yl)methyl)amino)-6-nitrobenzo[d][1,3]dioxol-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

[0214] 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]dioxol-4-yl)sulfonyl)-4-(2-((S)-2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide 158

[0215] (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]dioxol-4-yl)sulfonyl)-4-(2-(2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide 159

[0216] (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]dioxol-4-yl)sulfonyl)benzamide 160

[0217] N-((7-((((S)-1,4-dioxan-2-yl)methyl)amino)-6-nitrobenzo[d][1,3]dioxol-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

[0218] (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]dioxol-4-yl)sulfonyl)-4-(2-(2-(2-isopropylphenyl)-4-(4-methoxybenzyl)piperazin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide 162

[0219] 2-((1H-Pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((7-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-2,2-dimethyl-6-nitrobenzo[d][1,3]dioxol-4-yl)sulfonyl)-4-(2-((R)-2-(2-isopropylphenyl)-4-(4-methoxybenzyl)piperazin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide 163

[0220] (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]dioxol-4-yl)sulfonyl)-4-(2-(2-(2-isopropylphenyl)-4-(4-methoxybenzyl)piperazin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide 164

[0221] 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]dioxol-4-yl)sulfonyl)-4-(2-((R)-2-(2-isopropylphenyl)-4-(4-methoxybenzyl)piperazin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide 165

[0222] (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]dioxol-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

[0223] (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]dioxol-4-yl)sulfonyl)benzamide 167

[0224] (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]dioxol-4-yl)sulfonyl)benzamide 168

[0225] (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]dioxol-4-yl)sulfonyl)benzamide 169

[0226] (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]dioxol-4-yl)sulfonyl)benzamide 170

[0227] (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]dioxol-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

[0228] (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]dioxol-4-yl)sulfonyl)benzamide 172

[0229] (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]dioxol-4-yl)sulfonyl)benzamide 173

[0230] 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]dioxol-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

[0231] 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-nitrobenzo[d][1,3]dioxol-4-yl)sulfonyl)benzamide 175

[0232] 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-nitrobenzo[d][1,3]dioxol-4-yl)sulfonyl)benzamide 176

[0233] 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-nitrobenzo[d][1,3]dioxol-4-yl)sulfonyl)benzamide 177

[0234] 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-nitrobenzo[d][1,3]dioxol-4-yl)sulfonyl)benzamide 178

[0235] 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-nitrobenzo[d][1,3]dioxol-4-yl)sulfonyl)benzamide 179

[0236] 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]dioxol-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

[0237] (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

[0238] 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

[0239] 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

[0240] (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

[0241] (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

[0242] (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

[0243] (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

[0244] (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

[0245] (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

[0246] (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

[0247] (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

[0248] (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

[0249] (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

[0250] (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

[0251] (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

[0252] (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

[0253] (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

[0254] (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

[0255] (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

[0256] (R)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(4-(4-acetamidobenzyl)-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

[0257] (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-(methylsulfonamido)benzyl)piperazin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide 201

[0258] (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

[0259] (R)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(4-(benzo[d][1,3]dioxol-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

[0260] (R)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(4-(benzo[d][1,3]dioxol-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

[0261] (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]dioxol-4-yl)methyl)piperazin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide 205

[0262] (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]dioxan-5-yl)methyl)piperazin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide 206

[0263] (R)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(4-((2,3-dihydrobenzo[b][1,4]dioxan-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

[0264] (R)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(4-((2,3-dihydrobenzo[b][1,4]dioxan-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

[0265] (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

[0266] (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

[0267] (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

[0268] (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

[0269] (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

[0270] 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

[0271] 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

[0272] 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

[0273] 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

[0274] 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

[0275] 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

[0276] 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

[0277] 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

[0278] 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-((R)-4-(benzo[d][1,3]dioxol-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

[0279] 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]dioxol-4-yl)methyl)piperazin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide 223

[0280] 2-((1H-Pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-((R)-4-(benzo[d][1,3]dioxol-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

[0281] 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

[0282] 2-((1H-Pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-((R)-4-((2,3-dihydrobenzo[b][1,4]dioxan-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

[0283] 2-((1H-Pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-((R)-4-((2,3-dihydrobenzo[b][1,4]dioxan-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

[0284] 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]dioxan-5-yl)methyl)piperazin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide 228

[0285] 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

[0286] 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

[0287] 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

[0288] 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

[0289] 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

[0290] 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

[0291] 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

[0292] 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

[0293] 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

[0294] 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

[0295] (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

[0296] (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

[0297] 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

[0298] (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

[0299] (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

[0300] (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

[0301] (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

[0302] (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

[0303] (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

[0304] (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

[0305] (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

[0306] (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

[0307] (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

[0308] (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

[0309] (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

[0310] (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

[0311] (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

[0312] 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

[0313] (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

[0314] (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

[0315] 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

[0316] (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

[0317] (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

[0318] 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

[0319] (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

[0320] (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

[0321] (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

[0322] 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

[0323] (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

[0324] (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

[0325] Terminology Unless otherwise defined, all technical and scientific terms used in the present invention have the same meaning as those commonly understood by those skilled in the art. Unless otherwise stated, all patent documents, publications, etc. referred to in the present invention are incorporated by reference in their entirety. When there are multiple definitions for the same term in the present invention, the definition in this section shall prevail.

[0326] It is to be understood that the foregoing general description and the following detailed description are exemplary and explanatory only and are not intended to limit the scope of the claims. In the specification and the appended claims, the singular terms "a," "one," "the," "the," and the like, include plural references unless otherwise stated. Further, unless otherwise stated, the term "or" refers to "and / or." Furthermore, terms such as "comprises," "including," and the like, are not limiting.

[0327] "Substituted" means that a hydrogen atom is replaced with a substituent. Note that the substituent on a particular atom is limited by its valence. In the definitions section, "C i -C j " refers to a range inclusive of the starting and ending points, where i and j are integers representing the number of carbon atoms. For example, C 1- C4, C 1- C8, C 3- C8 etc.

[0328] C, H, O, S, N, F, Cl, Br, I, and the like relating to the groups and compounds described herein include their isotopes. At the same time, C, H, O, S, N, F, Cl, Br, I relating to the groups and compounds described herein may be optionally substituted with one or more corresponding isotopes, and carbon isotopes 12 C. 13 C. 14 C, hydrogen isotopes protium (H), deuterium (D), tritium (T), oxygen isotopes 16 O. 17 O. 18 O, an isotope of sulfur 32 S, 33 S, 34 S, 36 S, an isotope of nitrogen 14 N, 15 N, an isotope of fluorine 17 F, 19 F, an isotope of chlorine 35 Cl, 37 Cl, isotopes of bromine 79 Br, 81 These include, but are not limited to, Br, etc.

[0329] The term "alkyl group," as used herein, refers to a linear or branched saturated hydrocarbon group having from 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, and the like. The alkyl group may be substituted with one or more substituents, and when substituted multiple times, the substituents may be the same or different, and the substituents independently include D (deuterium), oxo, halogen, cyano group, nitro group, hydroxy group, amino group, aminoalkyl group, alkenyl group, alkynyl group, carboxy group, carboxylic acid ester group, acyl group, amido group, methylsulfonyl group, alkylamido group, C1-C8 alkyl group, C1-C8 alkoxy group, C1-C8 hydroxyalkyl group, C1-C8 alkylamino group, haloC1-C8 alkyl group, haloC1-C8 alkoxy group, haloC1-C8 hydroxyalkyl group, haloC1-C8 alkylamino group, C3-C 12 Cycloalkyl groups, halo C3-C 12 Cycloalkyl groups, cycloalkenyl groups, cycloalkynyl groups, alkoxycarbonyl groups, alkylthio groups, alkylsulfonyl groups, hydroxyalkylamide groups, sulfonamide groups, spiroalkyl groups, C6-C 12 Aryl groups, C5-C 14 Heteroaryl groups, C3-C 12 It is a heterocyclyl group.

[0330] The term "alkenyl group" as used herein refers to a straight or branched chain hydrocarbon group containing 1 to 8 carbon atoms and at least one C=C double bond, and includes vinyl, 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-pentenyl, 5-methyl-1-butenyl, 5-methyl-2 ... Examples of hexenyl groups include, but are not limited to, 1-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, and the like. The alkenyl group may be substituted with one or more substituents, and when multiply substituted, the substituents may be the same or different, and the substituents are independently D, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, halohydroxyalkyl, alkylamino, haloalkylamino, cycloalkyl, halocycloalkyl, heterocyclyl, aryl, heteroaryl, hydroxy, halogen, cyano, nitro, amino, aminoalkyl, carboxy, amido, sulfonamido, or spiroalkyl.

[0331] The term "alkynyl group" as used herein refers to a straight or branched chain hydrocarbon group having 1 to 8 carbon atoms and containing at least one C≡C triple bond, and includes ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 3-methyl-1-butyne, 4-methyl-1-butyne, 2-methyl-3-butyne, 1-methyl-4-butyne, 1-hexyl, 1-methyl-2-butyne, 1-methyl-3-butyne, 1-methyl-4-butyne, 1-methyl-2 ... Examples of hexynyl include, but are not limited to, 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-heptyl, 2-heptyl, 3-heptyl, 4-heptyl, 5-heptyl, 2-methyl-3-hexynyl, 3-methyl-1-hexynyl, 3,3-dimethyl-1-hexynyl, 4-methyl-1-hexynyl, and the like. The alkynyl group may be substituted with one or more substituents, and when multiply substituted, the substituents may be the same or different, and the substituents are independently D, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, halohydroxyalkyl, alkylamino, haloalkylamino, cycloalkyl, halocycloalkyl, heterocyclyl, aryl, heteroaryl, hydroxy, halogen, cyano, nitro, amino, aminoalkyl, carboxy, amido, sulfonamido, or spiroalkyl.

[0332] As used herein, the terms "halogen" and "halo" refer to fluorine, chlorine, bromine and iodine, preferably fluorine, chlorine and iodine.

[0333] The term "alkoxy group" as used herein refers to an alkyl group -O-, where alkyl is as defined above. Examples of "alkoxy group" as used herein include, but are not limited to, methoxy group, ethoxy group, n-propoxy group, isopropoxy group, n-butoxy group, sec-butoxy group, tert-butoxy group, pentoxy group, 2-pentoxy group, isopentoxy group, neopentoxy group, hexoxy group, 2-hexoxy group, 3-hexoxy group, 3-methylpentoxy group, and the like. The term "alkoxy group" further includes substituted alkoxy groups, and the substituents are D, halogen, oxo, amino, hydroxy, cyano, nitro, carboxy, amido, sulfonamido, spiroalkyl, C1-C8 alkyl, C1-C8 hydroxyalkyl, C1-C8 alkoxy, C1-C8 alkylamino, haloC1-C8 alkyl, haloC1-C8 hydroxyalkyl, haloC1-C8 alkoxy, haloC1-C8 alkylamino, C3-C 12 Cycloalkyl groups, C3-C 12 Heterocyclyl groups, C6-C 12 Aryl groups, C5-C 14 It may also be a heteroaryl group.

[0334] The term "hydroxyalkyl group" as used herein refers to an -alkyl group -OH, where alkyl is as defined above. Examples of "hydroxyalkyl group" as used herein include, but are not limited to, a hydroxymethyl group, a hydroxyethyl group, a hydroxypropyl group, a hydroxyisopropyl group, a hydroxybutyl group, a hydroxypentyl group, and the like. "Hydroxyalkyl group" further includes substituted hydroxyalkyl groups, where the substituents are D, halogen, oxo, amino group, hydroxy group, cyano group, nitro group, carboxy group, amido group, sulfonamido group, spiroalkyl group, C1-C8 alkyl group, C1-C8 hydroxyalkyl group, C1-C8 alkoxy group, C1-C8 alkylamino group, haloC1-C8 alkyl group, haloC1-C8 hydroxyalkyl group, haloC1-C8 alkoxy group, haloC1-C8 alkylamino group, C3-C 12Cycloalkyl groups, C3-C 12 Heterocyclyl groups, C6-C 12 Aryl groups, C5-C 14 It may also be a heteroaryl group.

[0335] The term "aminoalkyl group" as used herein refers to NH2-alkyl group-, where alkyl is as defined above. Examples of "aminoalkyl group" as used herein include, but are not limited to, aminomethyl group, aminoethyl group, aminopropyl group, aminoisopropyl group, aminobutyl group, aminopentyl group, and the like. "Aminoalkyl group" further includes substituted aminoalkyl groups, where the substituents are D, halogen, oxo, amino group, hydroxy group, cyano group, nitro group, carboxy group, amido group, sulfonamido group, spiroalkyl group, C1-C8 alkyl group, C1-C8 hydroxyalkyl group, C1-C8 alkoxy group, C1-C8 alkylamino group, haloC1-C8 alkyl group, haloC1-C8 hydroxyalkyl group, haloC1-C8 alkoxy group, haloC1-C8 alkylamino group, C3-C 12 Cycloalkyl groups, C3-C 12 Heterocyclyl groups, C6-C 12 Aryl groups, C5-C 14 It may be a heteroaryl group, and the substituent may be substituted on the alkyl group or on the N.

[0336] The term "alkylamino group" as used herein refers to the alkyl group -NH-, where alkyl is as defined above. Examples of "alkylamino group" as used herein include, but are not limited to, methylamino group, ethylamino group, propylamino group, isopropylamino group, butylamino group, pentylamino group, etc. "Alkylamino group" further includes substituted alkylamino groups, where the substituents are D, halogen, oxo, amino group, hydroxy group, cyano group, nitro group, carboxy group, amido group, sulfonamido group, spiroalkyl group, C1-C8 alkyl group, C1-C8 hydroxyalkyl group, C1-C8 alkoxy group, C1-C8 alkylamino group, haloC1-C8 alkyl group, haloC1-C8 hydroxyalkyl group, haloC1-C8 alkoxy group, haloC1-C8 alkylamino group, C3-C 12 Cycloalkyl groups, C3-C 12 Heterocyclyl groups, C6-C 12 Aryl groups, C5-C 14 It may be a heteroaryl group, and the substituent may be substituted on the alkyl group or on the N.

[0337] The term "cycloalkyl group," as used herein, refers to a non-aromatic monovalent hydrocarbon group, monocyclic or polycyclic (two monocyclic rings connected by a chemical bond or bridged or spirocyclic or fused) having 3 to 12 carbon atoms, and which may have one or more chemical bonds that are double or triple bonds. The term "cycloalkyl group" includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, octahydroindenyl, decahydronaphthalene, 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. groups, bicyclo[3.2.1]octanyl, bicyclo[5.1.1]nonanyl, bicyclo[4.2.1]nonanyl, bicyclo[4.3.1]nonanyl, bicyclo[3.2.2]nonanyl, bicyclo[5.2.1]decanyl, bicyclo[4.2.2]decanyl, spiro[2.2]pentanyl, spiro[2.3]hexanyl, spiro[2.4]heptanyl, spiro[2.5]octanyl, spiro[2.6]nonanyl, spiro[3.5]nonanyl, spiro[3.4]octanyl, spiro[3.3]heptanyl, spiro[4.5]decanyl, spiro[4.4]nonanyl, and the like. The cycloalkyl group may be substituted with one or more substituents, and when substituted with a plurality of substituents, the substituents may be the same or different, and the substituents independently include D (deuterium), oxo, halogen, cyano group, nitro group, hydroxy group, amino group, aminoalkyl group, alkenyl group, alkynyl group, carboxy group, carboxylic acid ester group, acyl group, amido group, methylsulfonyl group, alkylamido group, C1-C8 alkyl group, C1-C8 alkoxy group, C1-C8 hydroxyalkyl group, C1-C8 alkylamino group, haloC1-C8 alkyl group, haloC1-C8 alkoxy group, haloC1-C8 hydroxyalkyl group, haloC1-C8 alkylamino group, C3-C12 Cycloalkyl groups, halo C3-C 12 Cycloalkyl groups, cycloalkenyl groups, cycloalkynyl groups, alkoxycarbonyl groups, alkylthio groups, alkylsulfonyl groups, hydroxyalkylamide groups, sulfonamide groups, spiroalkyl groups, C6-C 12 Aryl groups, C5-C 14 Heteroaryl groups, C3-C 12 It is a heterocyclyl group.

[0338] The term "cycloalkenyl group" as used herein refers to a monocyclic or polycyclic (two monocyclic rings are connected by a chemical bond or are bridged, spirocyclic, or fused) non-aromatic monovalent hydrocarbon group having 3 to 12 carbon atoms and containing at least one C=C double bond, and includes 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]hexa-1,4-di ...

[0033] Hept-1-enyl, spiro[3.3]hept-1,5-dienyl, spiro[3.4]oct-1-enyl, spiro[3.4]octa-1,6-dienyl, spiro[3.4]oct-5-enyl, spiro[3.4]oct-6-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, and when multiple substituents are present, the substituents may be the same or different, and the substituents independently include D (deuterium), oxo, halogen, cyano group, nitro group, hydroxy group, aminoalkyl group, alkenyl group, alkynyl group, carboxy group, carboxylic acid ester group, acyl group, amido group, methylsulfonyl group, alkylamido group, C1-C8 alkyl group, C1-C8 alkoxy group, C1-C8 hydroxyalkyl group, C1-C8 alkylamino group, haloC1-C8 alkyl group, haloC1-C8 alkoxy group, haloC1-C8 hydroxyalkyl group, haloC1-C8 alkylamino group, C3-C 12 Cycloalkyl groups, halo C3-C 12 Cycloalkyl groups, cycloalkenyl groups, cycloalkynyl groups, alkoxycarbonyl groups, alkylthio groups, alkylsulfonyl groups, hydroxyalkylamide groups, sulfonamide groups, spiroalkyl groups, C6-C 12 Aryl groups, C5-C 12Heteroaryl groups, C3-C 12 It is a heterocyclyl group.

[0339] The term "heterocyclyl group" as used herein refers to a monocyclic or polycyclic (two monocyclic rings connected by a chemical bond or bridged, spirocyclic or fused) non-aromatic hydrocarbon group having 3 to 12 cyclic atoms, having one or more heteroatoms selected from N, O and S, and optionally having one or more chemical bonds that are double or triple bonds. Heterocyclyl groups include pyranyl, piperidinyl, piperazinyl, morpholinyl, dioxanyl, oxiranyl, oxepinyl, oxacyclohexyl, oxacycloheptyl, oxacyclooctyl, aziridinyl, azetidinyl, pyrrolidinyl, azepanyl, azocanyl, thiirane, thiiranyl, azocanyl, oxepinyl, diazepinyl, thiazepinyl, dihydrofuranyl, dihydrothiophenyl ... tetrahydropyranyl group, tetrahydrofuranyl group, tetrahydrothiophenyl group, tetrahydropyranyl group, tetrahydrothiopyranyl group, tetrahydrothiazolyl group, tetrahydroimidazolyl group, hexahydropyridazinyl group, hexahydropyrimidyl group, 1-azaspiro[2.2]pentanyl group, 1-azaspiro[2.3]hexanyl group, 4-azaspiro[2.3]hexanyl group, 5-azaspiro[2.3]hexanyl group, 2-azaspiro[3.3]heptanyl group azaspiro[3.5]nonanyl group, 6-azaspiro[3.5]octanyl group, 2,6-diazaspiro[3.3]heptanyl group, 2-oxa-6-azaspiro[3.3]heptane, 1-azaspiro[2.5]octanyl group, 2-azaspiro[3.4]octanyl group, 6-azaspiro[3.4]octanyl group, 2,6-diazaspiro[3.4]octanyl group, 2-azaspiro[3.5]nonanyl group, 6-azaspiro[3.5]nonanyl group, 7-azaspiro[3.5]nonanyl group, 2,7-diazaspiro[3.5]nonanyl group, 2-oxaspiro[2.5]octanyl group, 2,6-diazaspiro[3.3]heptane, 2-oxaspiro[2.5]octanyl group, 2-azaspiro[3.4]octanyl group, 6-azaspiro[3.5]nonanyl group, 7-azaspiro[3.5]nonanyl group, 2,7-diazaspiro[3.5]nonanyl group, 7-azaspiro[3.5]nonanyl group, 1-azaspiro[4.4]nonanyl group, 2-azaspiro[4.4]nonanyl group, 8-azaspiro[4.5]decanyl group, 2,8-diazaspiro[4.5]decanyl group, 1-oxaspiro[2.2]pentanyl group, 1-oxaspiro[2.3]hexanyl group, 4-oxaspiro[2.3]hexanyl group, 5-oxaspiro[2.3]hexanyl group, 2-oxaspiro[3.3]heptanyl group, 1-oxaspiro[2.5]octanyl group, 2-oxaspiro[3.4]octanyl group, 6-oxaspiro[3.4]octanyl group, 2-oxaspiro[3.5]nonanyl group, 6-oxaspiro[3.5]nonanyl group, 7-oxaspiro[3.5]nonanyl group, 1-oxaspiro[4.4]nonanyl group, 2-oxaspiro[4.4]nonanyl group, 8-oxaspiro[4.5]decanyl group, decahydroquinolinyl group, decahydroisoquinolinyl group, 2-azabicyclo[1.1.1]pentanyl group azabicyclo[4.1.1]octanyl, azabicyclo[3.2.1]octanyl, azabicyclo[3.2.1]octanyl, and the like. The heterocyclyl group may be substituted with one or more substituents, and when multiply substituted, the substituents may be the same or different, and the substituents may independently be D (deuterium), oxo, halogen, cyano group, nitro group, hydroxy group, amino group, aminoalkyl group, alkenyl group, alkynyl group, carboxy group, carboxylic acid ester group, acyl group, amido group, methylsulfonyl group, alkylamido group, C1-C8 alkyl group, C1-C8 alkoxy group, C1-C8 hydroxyalkyl group, C1-C8 alkylamino group, haloC1-C8 alkyl group, haloC1-C8 alkoxy group, haloC1-C8 hydroxyalkyl group, haloC1-C8 alkylamino group, C3-C. 12 Cycloalkyl groups, halo C3-C 12 Cycloalkyl groups, alkoxycarbonyl groups, alkylthio groups, alkylsulfonyl groups, hydroxyalkylamide groups, sulfonamide groups, spiroalkyl groups, C6-C 12 Aryl groups, C5-C 14 Heteroaryl groups, C3-C 12 It is a heterocyclyl group.

[0340] The term "aryl group" as used herein refers to a carbocyclic or fused polycyclic aromatic hydrocarbon group having 6 to 12 carbon atoms (in the case of a fused polycyclic ring, one of the fused rings may be partially saturated), including, but not limited to, a benzene ring, a naphthalene ring, an anthracene ring, an indene ring, a hydroindene group (indane group), a dihydronaphthalene ring, a tetrahydronaphthalene ring, and the like. The aryl group may be unsubstituted or substituted, and may be monosubstituted (e.g., ortho-, meta-, or para-substituted), disubstituted, trisubstituted, etc. When multiply substituted, the substituents may be the same or different, and the substituents may independently be D (deuterium), halogen, cyano, nitro, hydroxy, amino, aminoalkyl, alkenyl, alkynyl, carboxy, acyl, amido, alkylamido, C1-C8 alkyl, C1-C8 alkoxy, C1-C8 hydroxyalkyl, C1-C8 alkylamino, haloC1-C8 alkyl, haloC1-C8 alkoxy, haloC1-C8 hydroxyalkyl, haloC1-C8 alkylamino, C3-C 12 Cycloalkyl groups, halo C3-C 12 Cycloalkyl groups, alkoxycarbonyl groups, alkylthio groups, alkylsulfonyl groups, hydroxyalkylamide groups, sulfonamide groups, spiroalkyl groups, C6-C 12 Aryl groups, C5-C 14 Heteroaryl groups, C3-C 12 It is a heterocyclyl group.

[0341] The term "heteroaryl group" as used herein refers to a monocyclic or fused polycyclic aromatic hydrocarbon group having 5 to 14 cyclic atoms (in the case of a fused polycyclic group, one of the fused rings may be partially saturated), which corresponds to the above-mentioned "aryl group" in which one or more carbon atoms are replaced with a heteroatom such as N, O, or S. The heteroaryl ring may be monocyclic or bicyclic, i.e., formed by the fusion of two rings. Examples of the heteroaryl group include a pyridyl group, a pyrimidinyl group, a pyrazinyl group, a pyridazinyl group, a triazinyl group, an isoxazolyl group, an isothiazolyl group, a pyrazolyl group, a thiazolyl group, a thienyl group, a furanyl group, a triazolyl group, an oxazolyl group, an imidazolyl group, an indazolyl group, an indolizinyl group, an indolyl group, an indolinyl group, an isoindolinyl group, a quinolinyl group, an isoquinolinyl group, a quinoxalinyl group, a quinazolinyl group, a dihydroquinolinyl group, a tetrahydroquinolinyl group, a dihydroisoquinolinyl group, a tetrahydroisoquinolinyl group, a cinnolinyl group, a pteridinyl group, a purinyl group, a benzimidazolyl group, a benzofuranyl group, a benzothienyl group, a benzothiazolyl group, a benzotriazolyl group, a benzotriazinyl group, a benzoxadiazolyl group, benzoxazolyl group, benzisoxazolyl group, imidazopyridyl group, imidazothiazolyl group, pyrrolopyridyl group, thienopyrrolyl group, thienothienyl group, thienopyridyl group, thienopyrimidinyl group, pyrazolopyrimidinyl group, pyrrolopyrrolyl group, pyrrolopyrimidinyl group, pyrrolopyridazinyl group, pyrrolopyrazinyl group, imidazopyrimidinyl group, imidazopyrazinyl group, i These include, but are not limited to, midazopyridazinyl groups, pyrazolopyridyl groups, pyrazolopyridazinyl groups, pyrazolopyrazinyl groups, pyrimidopyridyl groups, pyrimidopyrazinyl groups, pyrimidopyridazinyl groups, pyrimidopyrimidinyl groups, pyridopyridyl groups, pyridopyrazinyl groups, pyridopyridazinyl groups, pyridazinopyridazinyl groups, pyridazinopyrazinyl groups, pyrazinopyrazinyl groups, and the like.The heteroaryl group may be unsubstituted, mono-substituted, or multiply substituted. When multiply substituted, the substituents may be the same or different, and the substituents are independently selected from D (deuterium), halogen, cyano group, nitro group, amino group, aminoalkyl group, hydroxy group, carboxy group, carboxylic acid ester group, acyl group, amido group, alkylamido group, alkoxycarbonyl group, alkylthio group, alkylsulfonyl group, hydroxyalkylamido group, sulfonamido group, spiroalkyl group, C1-C8 alkyl group, C1-C8 hydroxyalkyl group, C1-C8 alkoxy group, C1-C8 alkylamino group, haloC1-C8 alkyl group, haloC1-C8 hydroxyalkyl group, haloC1-C8 alkoxy group, haloC1-C8 alkylamino group, C3-C. 12 Cycloalkyl groups, halo C3-C 12 Cycloalkyl groups, C3-C 12 Heterocyclyl groups, C6-C 12 Aryl groups, C5-C 14 It is a heteroaryl group.

[0342] The terms "spiro ring" and "spirocyclic group" as used herein refer to a polycyclic structure in which at least two rings share one atom (typically a C atom), one or more chemical bonds in the polycyclic structure may be double or triple bonds, and one or more heteroatoms may be present. Spirocyclic groups include cyclobutylspiroazetidinyl groups, cyclobutylspiroaziridinyl groups, cyclobutylspiroazacyclohexyl groups, cyclopentylspiroazetidinyl groups, cyclopentylspiroaziridinyl groups, cyclopentylspiroazacyclohexyl groups, cyclohexylspiroazetidinyl groups, cyclohexylspiroaziridinyl groups, cyclohexylspiroazacyclohexyl groups, azetidinylspiroazetidinyl groups, azetidinylspiroaziridinyl groups, azetidinylspiroazacyclohexyl groups, aziridinyl groups, These include, but are not limited to, arylspiroazetidinyl groups, aziridinylspiroaziridinyl groups, aziridinylspiroazacyclohexyl groups, azacyclohexylspiroazetidinyl groups, azacyclohexylspiroaziridinyl groups, cyclohexylspiroazacyclohexyl groups, cyclobutylspiropiperidinyl groups, cyclopentylspiropiperidinyl groups, cyclohexylspiropiperidinyl groups, azetidinylspiropiperidinyl groups, aziridinylspiropiperidinyl groups, azabicyclocyclohexylspiropiperidinyl groups, and the like. The spirocyclic group may be unsubstituted, mono-substituted, or multiply substituted. When multiply substituted, the substituents may be the same or different, and the substituents independently include D (deuterium), oxo, halogen, cyano group, nitro group, hydroxy group, amino group, aminoalkyl group, alkenyl group, alkynyl group, carboxy group, carboxylic acid ester group, acyl group, amido group, methylsulfonyl group, alkylamido group, C1-C8 alkyl group, C1-C8 alkoxy group, C1-C8 hydroxyalkyl group, C1-C8 alkylamino group, haloC1-C8 alkyl group, haloC1-C8 alkoxy group, haloC1-C8 hydroxyalkyl group, haloC1-C8 alkylamino group, C3-C 12 Cycloalkyl groups, halo C3-C 12Cycloalkyl groups, cycloalkenyl groups, cycloalkynyl groups, alkoxycarbonyl groups, alkylthio groups, alkylsulfonyl groups, hydroxyalkylamide groups, sulfonamide groups, spiroalkyl groups, C6-C 12 Aryl groups, C5-C 14 Heteroaryl groups, C3-C 12 It is a heterocyclyl group.

[0343] As used herein, the term "bridged cyclic group" refers to a polycyclic structure in which at least two rings in the polycyclic structure share two or more atoms, one or more chemical bonds in the polycyclic structure may be double or triple bonds, and one or more heteroatoms may be present. The bridged cyclic group may be unsubstituted, mono- or polysubstituted, and if polysubstituted, the substituents may be the same or different, and the substituents may independently be D (deuterium), oxo, halogen, cyano, nitro, hydroxy, amino, aminoalkyl, alkenyl, alkynyl, carboxy, carboxylic acid ester, acyl, amido, methylsulfonyl, alkylamido, C1-C8 alkyl, C1-C8 alkoxy, C1-C8 hydroxyalkyl, C1-C8 alkylamino, haloC1-C8 alkyl, haloC1-C8 alkoxy, haloC1-C8 hydroxyalkyl, haloC1-C8 alkylamino, C3-C 12 Cycloalkyl groups, halo C3-C 12 Cycloalkyl groups, cycloalkenyl groups, cycloalkynyl groups, alkoxycarbonyl groups, alkylthio groups, alkylsulfonyl groups, hydroxyalkylamide groups, sulfonamide groups, spiroalkyl groups, C6-C 12 Aryl groups, C5-C 14 Heteroaryl groups, C3-C 12 It is a heterocyclyl group.

[0344] The term "fused bicyclic group," as used herein, refers to a bicyclic group of 5 to 14 carbon atoms, connected by a chemical bond between the two rings, wherein one or more of the chemical bonds in the bicyclic structure may be double or triple bonds, and wherein one or more heteroatoms may be present, including, but not limited to, N, O, S, etc. The "fused bicyclic group" may be unsubstituted, mono-substituted, or multiply substituted, and when multiply substituted, the substituents may be the same or different, and the substituents independently include D (deuterium), oxo, halogen, cyano group, nitro group, hydroxy group, amino group, aminoalkyl group, alkenyl group, alkynyl group, carboxy group, carboxylic acid ester group, acyl group, amido group, methylsulfonyl group, alkylamido group, C1-C8 alkyl group, C1-C8 alkoxy group, C1-C8 hydroxyalkyl group, C1-C8 alkylamino group, haloC1-C8 alkyl group, haloC1-C8 alkoxy group, haloC1-C8 hydroxyalkyl group, haloC1-C8 alkylamino group, C3-C 12 Cycloalkyl groups, halo C3-C 12 Cycloalkyl group, cycloalkenyl group, cycloalkynyl group, alkoxycarbonyl group, alkylthio group, alkylsulfonyl group, hydroxyalkylamide group, sulfonamide group, C6-C 12 Aryl groups, C5-C 14 Heteroaryl groups, C3-C 12 It is a heterocyclyl group.

[0345] As used herein, the terms "alkylcarbonyl" and "alkylcarbonyl group" refer to the alkyl group -C(O)-, where alkyl is as defined above. The term "alkylcarbonyl group" further includes substituted alkylcarbonyl groups, where the substituents are D, halogen, oxo, amino, hydroxy, cyano, nitro, carboxy, amido, sulfonamido, spiroalkyl, C1-C8 alkyl, C1-C8 hydroxyalkyl, C1-C8 alkoxy, C1-C8 alkylamino, haloC1-C8 alkyl, haloC1-C8 hydroxyalkyl, haloC1-C8 alkoxy, haloC1-C8 alkylamino, C3-C12 Cycloalkyl groups, C3-C 12 Heterocyclyl groups, C6-C 12 Aryl groups, C5-C 14 It may be a heteroaryl group. In the formula, "C(O)" represents C=O.

[0346] The term "alkoxycarbonyl group" as used herein refers to the alkyl group -OC(O)-, where alkyl is as defined above. "Alkoxycarbonyl group" further includes substituted alkoxycarbonyl groups, where the substituents are D, halogen, oxo, amino, hydroxy, cyano, nitro, carboxy, amido, sulfonamido, spiroalkyl, C1-C8 alkyl, C1-C8 hydroxyalkyl, C1-C8 alkoxy, C1-C8 alkylamino, haloC1-C8 alkyl, haloC1-C8 hydroxyalkyl, haloC1-C8 alkoxy, haloC1-C8 alkylamino, C3-C 12 Cycloalkyl groups, C3-C 12 Heterocyclyl groups, C6-C 12 Aryl groups, C5-C 14 It may be a heteroaryl group. In the formula, "C(O)" represents C=O.

[0347] The term "alkylthio group" as used herein refers to the alkyl group -S-, where alkyl is as defined above. Alkylthio groups include, but are not limited to, methylthio groups, ethylthio groups, propylthio groups, butylthio groups, and the like.

[0348] As used herein, the term "alkanoyl group" refers to the alkyl group -C(O)-, where alkyl is as defined above.

[0349] The term "alkylsulfonyl group," as used herein, refers to the alkyl group -S(O)2-, where alkyl is as defined above.

[0350] The term "haloalkyl group" as used herein refers to a linear or branched alkyl group substituted with a halogen (preferably fluorine, chlorine, bromine, or iodine), and "alkyl group" is as defined above. Examples of "haloalkyl group" as used herein include, but are not limited to, a fluoromethyl group, a difluoromethyl group, a trifluoromethyl group, a chloromethyl group, a dichloromethyl group, a trichloromethyl group, a 2,2,2-trifluoroethyl group, a 2-fluoroethyl group, a 2-chloroethyl group, a tetrafluoroethyl group, a pentafluoroethyl group, a fluoropropyl group, a difluoropropyl group, a trifluoropropyl group, a chloropropyl group, a fluorobutyl group, and the like. A "haloalkyl group" may be substituted one or more times with a halogen.

[0351] The term "halohydroxyalkyl group," as used herein, refers to a hydroxyalkyl group substituted with a halogen (preferably fluorine, chlorine, bromine, or iodine), where hydroxyalkyl group is as defined above. A "halohydroxyalkyl group" may be substituted one or more times with a halogen.

[0352] The term "haloalkoxy group," as used herein, refers to an alkoxy group substituted with a halogen (preferably fluorine, chlorine, bromine, or iodine), where the alkoxy group is as defined above. A "haloalkoxy group" may be substituted one or more times with a halogen.

[0353] The term "haloalkylamino group" as used herein refers to an alkylamino group substituted with a halogen (preferably fluorine, chlorine, bromine, or iodine), where the alkylamino group is as defined above. The "haloalkylamino group" may be substituted one or more times with a halogen.

[0354] As used herein, the term "pharmaceutically acceptable salt" refers to a salt formed with a compound of the present invention and an acid or base, which is suitable for use as a drug. Pharmaceutically acceptable salts include inorganic salts and organic salts. A preferred type of salt is a salt formed with a 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, cucoic 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 type of salt is a salt formed with a 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 the like; organic bases such as ammonia, triethylamine, diethylamine, piperazine, guanidine, diethanolamine, and the like.

[0355] The second object of the present invention is to provide a pharmaceutical composition comprising one or more of the compounds described in any of the above technical solutions, which may be composed of one or more of the compounds described in any of the above technical solutions and other compounds, or may be composed of one or more of the compounds described in any of the above technical solutions.

[0356] In another aspect, the present invention provides the use of a compound of general formula I-VII as disclosed herein in the manufacture of a medicament, alone or in combination with other drugs, to treat a disease, disorder, or condition that would benefit from the inhibition of BCL-2 activity.

[0357] In another embodiment, the compounds or pharmaceutically acceptable salts of the present invention may be used alone or in combination with other therapeutic agents.

[0358] In another embodiment, the compounds of the present invention are used in combination with other therapeutic agents, and the route of administration may be the same as that of the other drug, or may be different due to differences in physical and chemical properties. Thus, the compounds described herein and the other therapeutic agents may be administered simultaneously, sequentially, or separately.

[0359] In another aspect, the present invention provides the use of compounds of general formula I-VII disclosed herein that are expected to be effective in combination with one or more of the following drugs: alkylating agents, angiogenesis inhibitors, antibodies, antimetabolites, antimitotic agents, antiproliferative agents, antivirals, aurora kinase inhibitors, inhibitors of other apoptosis promoters (e.g., Bcl-xL, Bcl-w, and Bfl-1), 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 viral oncogene homolog (ErbB2) receptor inhibitors, growth factor inhibitors, heat shock protein (HSP)-90 inhibitors, histone deacetylase (HDAC) inhibitors, hormone therapy, immunologic agents, and inhibitors of apoptosis proteins. (IAPs), intercalating antibiotics, kinase inhibitors, kinesin inhibitors, Jak2 inhibitors, mammalian target of 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, chemotherapy platinum agents, polo-like kinase (Plk) inhibitors, phosphatidylinositol 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 similar.

[0360] In particular, said disease, disorder or condition includes, but is not limited to, an infectious disease, an immune disease, an inflammatory disease or a cell proliferative disease.

[0361] In particular, such infectious, immune, and inflammatory diseases include, but are not limited to, asthma, diseases caused by neutrophil chemotaxis (e.g., reperfusion injury in myocardial infarction and stroke and inflammatory arthritis), septic shock, T-cell disorders, immunosuppressant-related diseases (e.g., organ transplant rejection prophylaxis, graft-versus-host disease, lupus erythematosus, multiple sclerosis, and rheumatoid arthritis), pancreatitis, angiogenesis or angiogenesis-related diseases (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.

[0362] In particular, said cell proliferative disorders include cancerous proliferative disorders and non-cancerous proliferative disorders, and said disorders include, but are not limited to, hematological disorders and / or solid cancers, wherein said hematological tumors are preferably 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, Waldenström's macroglobulinemia, multiple myeloma, T-cell lymphoma, and said solid cancers are preferably one or more of osteosarcoma, skin cancer, breast cancer, renal 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 hyperplasia (BPH), melanoma.

[0363] The compounds of the present invention are administered in the form of pharmaceutical compositions and may be administered by any conventional route, and the compounds of the present invention may be formed into pharmaceutical preparations in the form of solid, semi-solid, liquid or gas, such as tablets, capsules, injections, suspensions, lotions, gels, ointments, creams, suppositories, inhalants, etc.

[0364] The compounds of the present invention may be made into pharmaceutical compositions of the compounds in free base or pharmaceutically acceptable salt form and at least one pharmaceutically acceptable carrier or diluent, which can be prepared in conventional manner by mixing, granulating, coating, dissolving or lyophilizing processes.

[0365] Experiments have demonstrated 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 cell proliferation disorders that benefit from the inhibition of the anti-apoptotic protein BCL-2.

[0366] Experiments have demonstrated that the compounds of the present invention have potent BCL2(G101V) inhibitory activity.

[0367] Experiments have demonstrated that the compounds of the present invention have potent BCL2(D103Y) inhibitory activity.

[0368] Experiments have demonstrated that the compounds of the present invention have significant growth inhibitory activity against RS4;11 cells.

[0369] Experiments have demonstrated that the compounds of the present invention have no apparent toxicity to platelets.

[0370] Experiments have demonstrated that the compounds of the present invention have no inhibitory effect on CYP3A4.

[0371] Experiments have demonstrated that the compounds of the present invention have good pharmacokinetic properties.

[0372] Experiments have demonstrated that the compounds of the present invention have high in vivo antitumor effects. DETAILED DESCRIPTION OF THE INVENTION

[0373] Intermediate 1: (S)-2-(2-isopropylphenyl)pyrrolidine JPEG0007765790000023.jpg60109

[0374] Synthesis Step 1: (tert-butyl (S)-2-(2-isopropylphenyl)pyrrolidine-1-carboxylate (Intermediate 1-1)

[0375] (S)-tert-butyl 2-(2-bromophenyl)pyrrolidine-1-carboxylate (4.5 g, 13.85 mmol) and isopropylboronic acid (3.1 g, 35.22 mmol) were dissolved in 15 mL of 1,4-dioxane and 3 mL of water. Under nitrogen protection, potassium carbonate (6 g, 43.40 mmol) and Pd(dppf)2Cl2 (0.9 g) were added, and the mixture was heated to reflux overnight. After the reaction was completed, the mixture was cooled to room temperature, EA was added, and the mixture was washed with water and saturated brine, respectively. The organic phase was separated, dried, filtered, and concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography to give the product tert-butyl (S)-2-(2-isopropylphenyl)pyrrolidine-1-carboxylate (3.4 g, 85% yield). ESI-MS (M+H) analysis revealed that the product was 3.4 g. + =290.2.

[0376] Synthesis Step 2: (S)-2-(2-isopropylphenyl)pyrrolidine (Intermediate 1) 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 overnight at room temperature. After the reaction was completed, the mixture was concentrated under reduced pressure to obtain 1.92 g of colorless oily intermediate 1 product, with a yield of 97%. ESI-MS (M+H) + = 190.2.

[0377] Intermediate 2: 4-((dimethylamino)methyl)-3-methoxybenzaldehyde JPEG0007765790000024.jpg80127

[0378] Synthesis Step 1: 1-(4-bromo-2-methoxyphenyl)-N,N-dimethylmethanamine (Intermediate 2-1) 4-Bromo-2-methoxybenzaldehyde (3 g, 13.95 mmol) was dissolved in 50 mL of DCM, and a 2 mol / L solution of dimethylamine in tetrahydrofuran (8.4 mL, 16.74 mmol) was added. The mixture was stirred at room temperature for 30 min. STAB (3.85 g, 18.14 mmol) was added and the mixture was allowed to react at room temperature for 4 h. After the reaction was completed, the mixture was extracted with saturated aqueous sodium bicarbonate. The DCM phase was separated and concentrated under reduced pressure. The resulting crude product was purified by column chromatography to obtain 1.8 g of the product, 1-(4-bromo-2-methoxyphenyl)-N,N-dimethylmethanamine, in a 53% yield. This was determined by ESI-MS (M+H). + = 244.0.

[0379] Synthesis Step 2: 4-((Dimethylamino)methyl)-3-methoxybenzaldehyde (Intermediate 2) Intermediate 2-1 (1.8 g, 7.39 mmol) was dissolved in 30 mL of anhydrous THF, and the system was cooled to -70 °C. 2.5 mol / L n-butyllithium hexane solution (3.6 mL, 8.87 mmol) was slowly added dropwise. The system was kept at -70 °C for 1 hour, and then anhydrous DMF (1 mL, 14.78 mmol) was added. The system was kept at -70 °C for 1 hour, and then the temperature was lowered to room temperature. Water was added to quench the reaction, and EA was added for extraction (100 ml * 2). The organic phases were separated and combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting crude product was purified by column chromatography to obtain 871 mg of intermediate 2 product, with a yield of 61%. ESI-MS (M+H) + = 194.1.

[0380] Intermediate 3: 3-Methoxy-4-(pyrrolidin-1-ylmethyl)benzaldehyde JPEG0007765790000025.jpg76144 Referring to the synthesis route and method of intermediate 2, 4-bromo-2-methoxybenzaldehyde in synthesis step 1 was replaced with 5-bromo-2-methoxybenzaldehyde to obtain intermediate 3, which was synthesized by ESI-MS (M+H) + =194.1.

[0381] The following intermediate structure was obtained by synthesis with reference to the synthesis routes and methods of Intermediates 2 and 3. JPEG0007765790000026.jpg143170

[0382] Intermediate 8: 4-(((2,4-dimethoxybenzyl)(methyl)amino)methyl)benzaldehyde JPEG0007765790000027.jpg95145

[0383] Synthesis Step 1: N-(4-(diethoxymethyl)benzyl)-1-(2,4-dimethoxyphenyl)-N-methylmethanamine (Intermediate 8-1) 4-(diethoxymethyl)benzaldehyde (500 mg, 2.4 mmol) was dissolved in 20 mL of DCM, and 1-(2,4-dimethoxyphenyl)-N-methylmethanamine (522 mg, 2.88 mmol) and STAB (1.5 g, 7.2 mmol) were added in that order. The mixture was allowed to react at room temperature for 10 h. The reaction was monitored by TLC, and the DCM phase was extracted with water. The DCM phase was separated and dried over anhydrous sodium sulfate. The resulting crude product was purified by column chromatography to give 600 mg of N-(4-(diethoxymethyl)benzyl)-1-(2,4-dimethoxyphenyl)-N-methylmethanamine in 67% yield. This was determined by ESI-MS (M+H). + = 374.2.

[0384] Synthesis Step 2: 4-(((2,4-Dimethoxybenzyl)(methyl)amino)methyl)benzaldehyde (Intermediate 8) Intermediate 8-1 (600 mg, 1.6 mmol) was dissolved in 10 mL of THF, and 10 mL of 2N HCl aqueous solution was added. After stirring at room temperature for 1 h, the THF was concentrated to remove the residue. EA and water were added for extraction. The organic phase was separated and dried over anhydrous sodium sulfate. The resulting crude product was purified by column chromatography to obtain 426.3 mg of intermediate 8 product, with a yield of 89%. ESI-MS (M+H) + = 300.2.

[0385] Intermediate 9: 3-(2-isopropylphenyl)-1-(4-methoxybenzyl)piperazine JPEG0007765790000028.jpg61115

[0386] Synthetic Step 1: (2-Isopropylphenyl)boronic Acid (Intermediate 9-1) 1-Bromo-2-isopropylbenzene (20 g, 0.10 mol) was dissolved in 200 mL of THF and stirred at -80 °C for 10 min. Then, n-BuLi (44 mL, 0.11 mol) was added dropwise. After the addition was complete, the mixture was kept at -80 °C for 1 h. Then, 50 mL of THF containing triisopropyl borate was added dropwise. The mixture was kept at -80 °C for 1 h, then transferred to 20 °C and stirred for 1 h. At the same time, aqueous HCl (150 mL, 0.15 mol, 1N) was added dropwise and stirring was continued for 1 h. After the reaction was complete, EA was added for extraction. The organic phase was separated, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product (2-isopropylphenyl)boronic acid, which was used directly in the next step. ESI-MS (M+H) analysis revealed the following: + = 165.1.

[0387] Synthesis Step 2: 2-(2-isopropylphenyl)pyrazine (Intermediate 9-2) Intermediate 9-1 (16.5 g, 0.10 mol) was added to 150 mL of dioxane and 150 mL of water, stirred, and then clarified. 2-chloropyridine (13.80 g, 0.12 mol), Pd(PPh3)4 (1.74 g, 1.50 mmol), and Na2CO3 (21.20 g, 0.20 mol) were added to the mixture in this order, and the mixture was reacted at 90 °C for 12 h. After the reaction was completed, the mixture was cooled to room temperature, filtered through diatomaceous earth, and extracted with EA. The organic phase was separated, dried, filtered, and concentrated under reduced pressure. The resulting crude product was purified by column chromatography to obtain 13 g of 2-(2-isopropylphenyl)pyrazine as a colorless oil in a 65% yield. ESI-MS (M+H) analysis revealed that the product was a 65% yield. + = 199.1.

[0388] Synthesis Step 3: 2-(2-Isopropylphenyl)piperazine (Intermediate 9-3) Intermediate 9-2 (10.2 g, 51.55 mmol) was added to 150 mL of absolute ethanol and 10 mL of glacial acetic acid. After stirring and clearing, Pd / C (5 g) was added to the reaction mixture. The mixture was then placed under hydrogen gas (4 atm) at 60 °C for 10 h. After the reaction was complete, the diatomaceous earth was filtered off and washed with methanol (300 mL) and water (100 mL), respectively. The mixture was concentrated under reduced pressure to remove most of the methanol, extracted with EA, the aqueous phase was separated, and the pH was adjusted to 13-14 with 10% aqueous NaOH. The organic phase was then separated, dried, filtered, and concentrated under reduced pressure. The resulting crude product was purified by column chromatography to obtain 9.66 g of the product, 2-(2-isopropylphenyl)piperazine, in a 91% yield. ESI-MS (M+H) analysis revealed that the product was 2-(2-isopropylphenyl)piperazine. + = 205.2.

[0389] Synthesis Step 4: 3-(2-Isopropylphenyl)-1-(4-methoxybenzyl)piperazine (Intermediate 9) Intermediate 9-3 (2.00 g, 9.80 mmol) and 4-methoxybenzaldehyde (1.20 mL, 9.80 mmol) were dissolved in 40 mL of DCM, STAB (6.20 g, 29.40 mmol) was added, and the mixture was allowed to react at room temperature for 3 h. After the reaction was completed, DCM was added and the mixture was extracted. The organic phase was separated, dried, filtered, and concentrated under reduced pressure. The resulting crude product was purified by column chromatography to obtain 1.7 g of solid intermediate 9 in a 53% yield. The ESI-MS (M+H) analysis revealed that the solid intermediate 9 was 1.7 g. + = 325.2.

[0390] Intermediate 10: (R)-3-(2-isopropylphenyl)-1-(4-methoxybenzyl)piperazine JPEG0007765790000029.jpg85161

[0391] Synthesis Step 1: (R)-2-(2-isopropylphenyl)piperazine (Intermediate 10-1) Intermediate 9-3 (2 g, 9.8 mmol) was dissolved in 650 mL of a mixed solvent of MeOH / EA (V / V = 1:10), N-acetyl-D-leucine (17 g, 98 mmol) was added, and the mixture was refluxed for 1 hour until the solution became clear. The mixture was then allowed to cool to room temperature and stirred for 16 hours. After the reaction was complete, the mixture was filtered. The filter cake was washed with ethyl acetate and then concentrated under reduced pressure at 45 °C for 1 hour to obtain approximately 15 g of crude product. The crude product was extracted three times with DCM / 1N aqueous NaOH (V / V = 3:2) and separated (100 mL * 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 5.3 g of (R)-2-(2-isopropylphenyl)piperazine in a 26.5% yield. ESI-MS (M+H) analysis revealed that the crude product was eluted with 2-(2-isopropylphenyl)piperazine. + = 205.2. 1 H-NMR-(400-MHz, Chloroform-d) δ 7.55 (dd, J = 7.6, 1.6 Hz, 1H), 7.30 - 7.10 (m, 3H), 4.06 (dd, J = 10.1, 2.7 Hz, 1H), 3.31 (hept, J = 6.9 Hz, 1H), 3.16 - 3.07 (m, 1H), 3.04 - 2.83 (m, 4H), 2.69 (dd, J = 12.1, 10.0 Hz, 1H), 1.23 (dd, J = 6.9, 1.9 Hz, 6H).

[0392] Synthesis Step 2: (R)-3-(2-isopropylphenyl)-1-(4-methoxybenzyl)piperazine (Intermediate 10) 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. STAB (7.8 g, 36.7 mmol) was then added and the mixture was stirred uniformly for 16 h at 0 °C. After the reaction was complete, DCM and water were added for extraction and separation. The organic phase was concentrated under reduced pressure, and the resulting crude product was purified by column chromatography to obtain 6.9 g of solid product, Intermediate 10, in an 87% yield. ESI-MS (M+H) analysis revealed that the solid product was 10. + = 325.2. 1H NMR (400 MHz, Chloroform-d) δ 7.53 (dd, J = 7.5, 1.3 Hz, 1H), 7.28 - 7.19 (m, 4H), 7.15 (ddd, J = 7.7, 6.5, 2.2 Hz, 1H), 6.87 - 6.80 (m, 2H), 4.33 (dd, J = 10.5, 2.7 Hz, 1H), 3.77 (s, 3H), 3.57 (d, J = 1.8 Hz, 2H), 3.24 - 3.06 (m, 3H), 2.91 (td, J = 12.2, 11.2, 2.3 Hz, 2H), 2.44 - 2.33 (m, 1H), 2.23 (dd, J = 11.8, 10.5 Hz, 1H), 1.22 (d, J = 6.7 Hz, 3H), 1.12 (d, J = 6.8 Hz, 3H).

[0393] Intermediate 11: 3-(2-isopropylphenyl)-1-(tetrahydro-2H-pyran-4-yl)piperazine JPEG0007765790000030.jpg56128

[0394] By referring to the synthesis route and method of intermediate 9, 4-methoxybenzaldehyde in synthesis step 4 is replaced with tetrahydro-4H-pyran-4-one to obtain intermediate 11. ESI-MS (M+H) + = 289.2.

[0395] Intermediate 12: (R)-3-(2-isopropylphenyl)-1-((6-methoxypyridin-3-yl)methyl)piperazine JPEG0007765790000031.jpg81147

[0396] Refer to the synthesis route and method of intermediate 10, and replace 4-methoxybenzaldehyde in synthesis step 2 with 6-methoxynicotinaldehyde to obtain intermediate 12. ESI-MS (M+H) + = 326.2.

[0397] The following intermediate structures were obtained by synthesis with reference to the synthetic routes and methods of intermediates 9 to 12. JPEG0007765790000032.jpg159170JPEG0007765790000033.jpg243170JPEG0007765790000034.jpg254170JPEG0007765790000035.jpg67170

[0398] Intermediate 55: 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-oxo-7-azaspiro[3.5]nonan-7-yl)benzoate JPEG0007765790000036.jpg54136

[0399] Synthetic Step 1: 7-Azaspiro[3.5]nonan-2-one trifluoroacetate (Intermediate 55-1) tert-Butyl 2-oxo-7-azaspiro[3.5]nonane-7-carboxylate (5 g, 20.6 mmol) was dissolved in 40 mL of DCM, and TFA (14 mL, 206 mmol) was added and the mixture was stirred for 2 h at 25° C. After completion of the reaction, the mixture was concentrated to remove the solvent and TFA, and used directly in the next step without further purification.

[0400] Synthesis Step 2: 2-Fluoro-4-(2-oxo-7-azaspiro[3.5]nonan-7-yl)benzoate (Intermediate 55-2) 2,4-Difluorobenzoate (3.5 g, 20.6 mmol) was dissolved in 100 mL of DMF, and then intermediate 55-1 (5.2 g, 20.6 mmol) and sodium carbonate (6.5 g, 61.8 mmol) were added in that order. The mixture was then reacted at 80 °C for 10 h. When TLC showed the reaction was complete, the mixture was concentrated to remove DMF, and extracted with EA and water. The organic phases were separated and combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting crude product was purified by column chromatography to give 4.7 g of the product, 2-fluoro-4-(2-oxo-7-azaspiro[3.5]nonan-7-yl)benzoate, in a 78% yield. ESI-MS (M+H) analysis revealed that the product was 2-fluoro-4-(2-oxo-7-azaspiro[3.5]nonan-7-yl)benzoate. + = 292.1.

[0401] Synthesis Step 3: 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-oxo-7-azaspiro[3.5]nonan-7-yl)benzoate (Intermediate 55) 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 reaction was carried out in a sealed tube at 130 °C for 8 h. When TLC showed the reaction was complete, the crude product was dried on an oil pump and purified by column chromatography. The crude product was slurried with PE to obtain 1.3 g of solid product, intermediate 55, in a 20% yield. ESI-MS (M+H) + = 406.2.

[0402] Intermediate 56: 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-5-fluoro-4-(2-oxo-7-azaspiro[3.5]nonan-7-yl)benzoate JPEG0007765790000037.jpg54126 Refer to the synthetic route and method for intermediate 55, and replace 2,4-difluorobenzoate with 2,4,5-trifluorobenzoate in synthesis step 2 to obtain intermediate 56. ESI-MS (M+H) + = 424.2. 1 H NMR (400 MHz, Chloroform-d) δ 10.09 (s, 1H), 8.12 (dd, J = 2.6, 0.4 Hz, 1H), 7.65 (d, J = 13.5 Hz, 1H), 7.49 (dd, J = 2.5, 0.6 Hz, 1H), 7.36 (dd, J = 3.5, 2.4 Hz, 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).

[0403] Intermediate 57: 2-((3-fluoro-1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-oxo-7-azaspiro[3.5]nonan-7-yl)benzoate JPEG0007765790000038.jpg53131

[0404] Synthesis Step 1: 5-Bromo-3-fluoro-1H-pyrrolo[2,3-b]pyridine (Intermediate 57-1) 5-Bromo-1H-pyrrolo[2,3-b]pyridine (20 g, 101.50 mmol) was dissolved in 400 mL of acetonitrile and 100 mL of acetic acid, and 1-chloromethyl-4-fluoro-1,4-diazabicyclo[2.2.2]octane bis(tetrafluoroboronic acid) salt (54 g, 152.25 mmol) was added and reacted at 90 °C for 16 h. When TLC showed the reaction was complete, the mixture was concentrated to remove acetonitrile and acetic acid. The residue was dissolved in EA and neutralized by slowly adding saturated aqueous sodium bicarbonate solution. The pH of the aqueous phase was adjusted to 8-9. The EA phases were separated, combined, dried, and concentrated. The resulting 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, in a 24% yield. ESI-MS (M+H) analysis revealed the product. + = 215.0.

[0405] Synthesis Step 2: 3-Fluoro-5-methoxy-1H-pyrrolo[2,3-b]pyridine (Intermediate 57-2) Intermediate 57-1 (5.2 g, 24.18 mmol) was dissolved in 100 mL of anhydrous DMF, and copper(I) bromide (6.9 g, 48.36 mmol) and sodium methoxide (3.9 g, 72.54 mmol) were added at room temperature. The mixture was then heated to 130 °C and reacted for 3 h. When TLC showed the reaction was complete, 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. The organic phases were separated and combined, dried over anhydrous sodium sulfate, filtered, and the resulting crude product was purified by column chromatography to give the product 3-fluoro-5-methoxy-1H-pyrrolo[2,3-b]pyridine 1.4 g in a 36% yield. ESI-MS (M+H) analysis revealed that the product was 3-fluoro-5-methoxy-1H-pyrrolo[2,3-b]pyridine 1.4 g.+ = 167.1.

[0406] Synthesis Step 3: 3-Fluoro-1H-pyrrolo[2,3-b]pyridin-5-ol (Intermediate 57-3) Intermediate 57-2 (1.4 g, 8.43 mmol) was dissolved in 30 mL of DCM, and the mixture was cooled to -20 °C. A solution of boron tribromide in DCM (6.4 g, 25.29 mmol) was slowly added dropwise, maintaining the internal temperature between -20 °C and -10 °C. After the addition, the mixture was incubated at -20 °C for 1 h. After the reaction was completed, the mixture was slowly poured into cold water, neutralized with saturated aqueous sodium bicarbonate to a pH between 7 and 9, and extracted with EA. The organic phase was separated, dried over anhydrous sodium sulfate, and filtered. The crude product was purified by column chromatography to obtain 743 mg of the product, 3-fluoro-1H-pyrrolo[2,3-b]pyridin-5-ol, in a 58% yield. ESI-MS (M+H) analysis revealed the following: + = 153.0.

[0407] Synthesis Step 4: 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) Referring to the synthesis route and method of intermediate 55, 1H-pyrrolo[2,3-b]pyridin-5-ol in synthesis step 3 was replaced with intermediate 57-3, and the target intermediate 57 was synthesized. + = 424.2.

[0408] The following intermediate structures were obtained by synthesis with reference to the synthetic routes and methods of intermediates 55 to 57. JPEG0007765790000039.jpg216170

[0409] Intermediate 61: 2-(3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-4-(2-oxo-7-azaspiro[3.5]nonan-7-yl)benzoate JPEG0007765790000040.jpg59132

[0410] Synthesis Step 1: 5-Bromo-6-fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine (Intermediate 61-1) 5-Bromo-6-fluoro-1H-pyrrolo[2,3-b]pyridine (10 g, 46.50 mmol) was dissolved in 200 mL of DMF, and 60% NaH (846.4 mg, 51.16 mmol) was added. After stirring at room temperature for 30 min, 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, filtered, and concentrated under reduced pressure. The resulting crude product was purified by column chromatography to obtain the product 5-bromo-6-fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine (13 g, 80% yield). ESI-MS (M+H) analysis revealed the following: + = 345.0.

[0411] 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) N-(3-hydroxypropyl)-4-methylbenzenesulfonamide (10.62 g, 46.32 mmol) was dissolved in 400 mL of THF and cooled to 0 °C. 60% NaH (2.3 g, 57.90 mmol) was added in small portions and allowed to react for 1 hour. Then, Intermediate 61-1 (8 g, 23.16 mmol) was added and allowed to react overnight at room temperature. After the reaction was completed, saturated ammonium chloride solution was added to quench the reaction. EA and water were added for extraction. The EA phase was separated, dried, filtered, and concentrated under reduced pressure. The resulting crude product was purified by column chromatography to obtain 5.8 g of N-(3-((5-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)oxy)propyl)-4-methylbenzenesulfonamide in a yield of 45%. ESI-MS (M+H) analysis revealed that the product was N-(3-((5-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)oxy)propyl)-4-methylbenzenesulfonamide in a yield of 45%. + = 554.1.

[0412] 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) Intermediate 61-2 (5.04 g, 9.1 mmol) was dissolved in 100 mL of DMSO, and 2-picolinic acid (900 mg, 7.3 mmol), copper iodide (2.1 g, 10.92 mmol), and potassium carbonate (3.8 g, 27.3 mmol) were added in that order. The mixture was then reacted at 140 °C overnight. After the reaction was completed, the mixture was extracted with EA and water. The EA phase was separated, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting crude product was purified by column chromatography to give 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]oxazepane, in a yield of 48.6%. ESI-MS (M+H) analysis revealed the following: + = 474.2.

[0413] 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) 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 the mixture was refluxed for 1 h. The reaction was then quenched with saturated aqueous ammonium chloride. EA and water were added for extraction. The EA phase was separated, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting crude product was purified by column chromatography to give 1.1 g of the product, 7-((2-(trimethylsilyl)ethoxy)methyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepane, in an 86% yield. ESI-MS (M+H) analysis revealed that the product was 7-((2-(trimethylsilyl)ethoxy)methyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepane). + = 320.2.

[0414] 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]oxazepin-1(7H)-yl)benzoate (Intermediate 61-5) 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), and Pd(dba) (144 mg, 0.16 mmol) were added in that order. The mixture was protected with nitrogen and reacted at 110 °C overnight. After the reaction was completed, the mixture was cooled to room temperature, and extracted with EA and water. The EA phase was separated, dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting crude product was purified by column chromatography to obtain 471 mg of the product, 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]oxazepin-1(7H)-yl)benzoate. The yield was 51%, and ESI-MS (M+H) indicated that the product was 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]oxazepin-1(7H)-yl)benzoate. The yield was 51%. + = 591.3.

[0415] Synthesis Step 6: 2-(3,4-Dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-4-(2-oxo-7-azaspiro[3.5]nonan-7-yl)benzoate (Intermediate 61) Intermediate 61-5 (471 mg, 0.80 mmol) was dissolved in 20 mL of THF, 30 mL of TBAF solution (1 mol / L THF solution) was added, and the mixture was heated under reflux overnight and then cooled to room temperature. EA and water were added for extraction, the EA phase was separated, dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting crude product was purified by column chromatography to give 326 mg of solid product, intermediate 61, in an 89% yield. ESI-MS (M+H) + = 461.2.

[0416] The following intermediate structure was obtained by synthesis with reference to the synthesis route and method of intermediate 61. JPEG0007765790000041.jpg126170

[0417] Intermediate 64: 4-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-3-nitrobenzenesulfonamide JPEG0007765790000042.jpg36119 (4-Fluorotetrahydro-2H-pyran-4-yl)methanamine (0.5 g, 5 mmol) was dissolved in 15 mL of THF, and 4-fluoro-3-nitrobenzenesulfonamide (1.1 g, 5 mmol) and triethylamine (4 g, 40 mmol) were added. The mixture was allowed to react at room temperature for 8 h. When TLC showed the reaction was complete, the mixture was concentrated and extracted with DCM / HO. The organic phase was separated, dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting crude product was purified by column chromatography to give 1.23 g of solid intermediate 64 in 74% yield. ESI-MS (M+H) analysis revealed the following: + = 334.1.

[0418] Intermediate 65: 4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrobenzenesulfonamide JPEG0007765790000043.jpg34118

[0419] Refer to the synthetic route and method of intermediate 64, and replace (4-fluorotetrahydro-2H-pyran-4-yl)methanamine with (1r,4r)-4-(aminomethyl)-1-methylcyclohex-1-ol to obtain intermediate 65. ESI-MS (M+H) + = 344.1.

[0420] Intermediate 66: 4-((4-fluoro-1-(oxacyclo-3-yl)piperidin-4-yl)methyl)amino)-3-nitrobenzenesulfonamide JPEG0007765790000044.jpg35134

[0421] Synthesis Step 1: tert-butyl 4-fluoro-4-(((2-nitro-4-sulfamoylphenyl)amino)methyl)piperidine-1-carboxylate (Intermediate 66-1) Referring to the synthesis route and method of intermediate 64, (4-fluorotetrahydro-2H-pyran-4-yl)methanamine was replaced with tert-butyl 4-(aminomethyl)-4-fluoropiperidine-1-carboxylate, and synthesis was carried out to obtain tert-butyl 4-fluoro-4-(((2-nitro-4-sulfamoylphenyl)amino)methyl)piperidine-1-carboxylate. ESI-MS (M+H) + =433.1.

[0422] Synthesis Step 2: 4-((4-fluoro-1-(oxacyclo-3-yl)piperidin-4-yl)methyl)amino)-3-nitrobenzenesulfonamide (Intermediate 66) Intermediate 66-1 (2 g, 4.62 mmol) was added to 30 mL of DCM, 15 mL of TFA was added, and the mixture was allowed to react at room temperature for 4 h. When TLC showed the reaction was complete, the reaction mixture was directly spun down to give 1.96 g of a yellow viscous liquid. The resulting yellow liquid product was dissolved in 20 mL of DCM, 3-oxetanone (475 mg, 6.58 mmol) was added, and the mixture was stirred at room temperature for 30 min. STAB (1.39 g, 6.58 mmol) was added, and the reaction was continued at room temperature for 2 h. When TLC showed the reaction was complete, the mixture was extracted with DCM and water. The organic phase was separated, dried, filtered, and concentrated under reduced pressure. The resulting crude product was purified by column chromatography to give 1.61 g of a yellow solid product (Intermediate 66) in 63% yield. ESI-MS (M+H) analysis revealed that the product was a yellow solid. + = 389.1.

[0423] The following intermediate structures were obtained by synthesis with reference to the synthetic routes and methods of intermediates 64 to 66. JPEG0007765790000045.jpg85170

[0424] Intermediate 70: 6-nitro-7-(((tetrahydro-2H-pyran-4-yl)methyl)amino)-1H-benzo[d]imidazole-4-sulfonamide JPEG0007765790000046.jpg63169

[0425] Synthesis Step 1: 4,7-Dibromo-1H-benzo[d]imidazole (Intermediate 70-1) 3,6-Dibromobenzene-1,2-diamine (4.5 g, 16.92 mmol) was dissolved in 100 mL of THF, trimethyl orthoformate (2.70 g, 25.38 mmol) was added, and after stirring for 5 min, p-toluenesulfonic acid (291 mg, 1.69 mmol) was added and the mixture was allowed to react at room temperature for 1 h. When TLC showed the reaction was complete, the mixture was filtered with suction, the solid was washed with mother liquor, and then dried in an oven at 60 °C to obtain 4.3 g of yellow solid product, 4,7-dibromo-1H-benzo[d]imidazole, in a 93% yield. ESI-MS (M+H) analysis revealed the reaction was complete. + = 274.9.

[0426] Synthesis Step 2: 4,7-Dibromo-6-nitro-1H-benzo[d]imidazole (Intermediate 70-2) At 0°C, intermediate 70-1 (4.30 g, 15.58 mmol) was dissolved in 45 mL of concentrated sulfuric acid. After stirring for 5 minutes, HNO3 (830 mL, 18.70 mmol) was slowly added dropwise. The temperature of the system was controlled between 0 and 10°C. After the addition was completed, the system was stirred for 1 hour at 0°C. After the reaction was completed, the reaction solution was slowly poured into cold aqueous ammonia to quench the reaction. The pH after quenching was approximately 8. The reaction was filtered with suction, the solid was washed with water, and then dried in an oven at 60°C to obtain 4 g of yellow solid product, 4,7-dibromo-6-nitro-1H-benzo[d]imidazole, in an 80% yield. ESI-MS (M+H) analysis revealed that the product was a yellow solid. + = 319.9.

[0427] Synthesis Step 3: 4-Bromo-6-nitro-N-((tetrahydro-2H-pyran-4-yl)methyl)-1H-benzo[d]imidazol-7-amine (Intermediate 70-3) Intermediate 70-2 (3 g, 9.35 mmol) was dissolved in 20 mL of dioxane, and (tetrahydro-2H-pyran-4-yl)methanamine (1.62 g, 14.03 mmol) and K2CO3 (3.9 g, 28.05 mmol) were added in that order. The mixture was then sealed and reacted at 120 °C for 48 h. When TLC showed the reaction was complete, the mixture was concentrated to remove dioxane, and extracted with water and EA. The organic phase was separated, dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting crude product was purified by column chromatography to give 2.9 g of yellow solid product, 4-bromo-6-nitro-N-((tetrahydro-2H-pyran-4-yl)methyl)-1H-benzo[d]imidazol-7-amine, in an 88% yield. ESI-MS (M+H) analysis revealed that the product was 4-bromo-6-nitro-N-((tetrahydro-2H-pyran-4-yl)methyl)-1H-benzo[d]imidazol-7-amine. + =355.0.

[0428] Synthesis Step 4: 4-(benzylthio)-6-nitro-N-((tetrahydro-2H-pyran-4-yl)methyl)-1H-benzo[d]imidazol-7-amine (Intermediate 70-4) 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(dba) (754 mg, 0.823 mmol), and DIPEA (3.2 g, 24.69 mmol) were added in that order. The reaction was then sealed at 110 °C for 16 h. After LCMS showed the reaction was complete, water and EA were added for extraction. The organic phase was separated, dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting crude product was purified by column chromatography to give 1.26 g of a yellow solid product, 4-(benzylthio)-6-nitro-N-((tetrahydro-2H-pyran-4-yl)methyl)-1H-benzo[d]imidazol-7-amine, in a 38.5% yield. ESI-MS (M+H) analysis revealed the reaction was complete. + = 399.1.

[0429] Synthesis Step 5: 6-Nitro-7-(((tetrahydro-2H-pyran-4-yl)methyl)amino)-1H-benzo[d]imidazole-4-sulfonamide (Intermediate 70) Add intermediate 70-4 (1.26 g, 3.17 mmol), MeCN (14 mL), HO (1.4 mL), and AcOH (0.7 mL) to a single-neck flask in this order. Cool the reaction mixture to 0 °C, add NCS (1.27 g, 9.51 mmol) in small portions, stir at 0 °C for 1 h, then transfer to room temperature and continue the reaction for 1 h. Next, add the reaction mixture dropwise to cold 25% aqueous ammonia (22.5 mL, 158.45 mmol) and continue the reaction with stirring at room temperature for 1 h. After the reaction was completed, add water to dilute the mixture. The aqueous phase was extracted with a 10% ethanol solution in ethyl acetate. The organic phase was separated, dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting crude product was purified by column chromatography to obtain 338 mg of intermediate 70, a yellow solid, in 30% yield. ESI-MS (M+H) analysis revealed the following: + = 356.1.

[0430] Intermediate 71: 7-(((4-fluoro-1-(oxetan-3-yl)piperidin-4-yl)methyl)amino)-6-nitro-1H-benzo[d]imidazole-4-sulfonamide JPEG0007765790000047.jpg48126

[0431] 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) Referring to the synthesis route and method of intermediate 70, in synthesis step 3, (tetrahydro-2H-pyran-4-yl)methanamine was replaced with 4-(aminomethyl)-4-fluoropiperidine-1-carboxylate to obtain tert-butyl 4-fluoro-4-(((6-nitro-4-sulfamoyl-1H-benzo[d]imidazol-7-yl)amino)methyl)piperidine-1-carboxylate, which was synthesized by ESI-MS (M+H). + = 473.2.

[0432] Synthesis Step 2: 7-(((4-fluoro-1-(oxetan-3-yl)piperidin-4-yl)methyl)amino)-6-nitro-1H-benzo[d]imidazole-4-sulfonamide (Intermediate 71) Intermediate 71-1 (190 mg, 0.40 mmol) was dissolved in 10 mL of DCM, 2 mL of trifluoroacetic acid was added, and the mixture was allowed to react at room temperature for 6 h. When TLC showed the reaction was complete, the reaction mixture was concentrated to give a yellow oil. The above product was dissolved in 10 mL of DCM, 3-oxetanone (44 mg, 0.60 mmol) was added, and the mixture was stirred 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. When TLC showed the reaction was complete, the mixture was extracted with DCM and water. The organic phase was separated, dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting crude product was purified by column chromatography to give 145 mg of a yellow solid product, intermediate 71, in an 85% yield. ESI-MS (M+H) analysis revealed that the product was a yellow solid. + = 429.1.

[0433] The following intermediate structures were obtained by synthesis with reference to the synthetic routes and methods of intermediates 70 and 71. JPEG0007765790000048.jpg177170JPEG0007765790000049.jpg209170

[0434] Intermediate 86: 6-nitro-7-(((tetrahydro-2H-pyran-4-yl)methyl)amino)benzo[d][1,3]dioxolane-4-sulfonamide JPEG0007765790000050.jpg44135

[0435] Synthesis Step 1: 2-Bromo-6-methoxy-3-nitrophenol (Intermediate 86-1) 2-Methoxy-5-nitrophenol (100 g, 591.2 mmol) was dissolved in 500 mL of glacial acetic acid, and 30 mL of Br2 was added dropwise at room temperature. The mixture was then reacted for 14 h at room temperature. After the reaction was complete, saturated sodium sulfite was added to quench the reaction, and water was added to precipitate a solid. The solid was filtered, washed with water, and dried under reduced pressure at 50 °C to obtain 99 g of brown solid crude product 2-bromo-6-methoxy-3-nitrophenol. The yield was 67.51%, as determined by ESI-MS (M+H). + =247.9.

[0436] Synthesis Step 2: 3-Bromo-4-nitrobenzene-1,2-diol (Intermediate 86-2) Intermediate 86-1 (99 g, 399.15 mmol) was dissolved in 1000 mL of dichloromethane, solid anhydrous AlCl3 (243 g, 1.82 mol) was added, and the mixture was heated to 40 °C and refluxed for 13 h. After the reaction was completed, the reaction mixture was poured into cold water, extracted with ethyl acetate, and the organic phase was separated and concentrated. The resulting crude product was separated by column chromatography to obtain the product 3-bromo-4-nitrobenzene-1,2-diol 82 g in 87.8% yield. ESI-MS (M+H) + =233.9.

[0437] Synthesis Step 3: 4-Bromo-5-nitrobenzo[d][1,3]dioxolane (Intermediate 86-3) Intermediate 86-2 (10 g, 42.74 mmol) was dissolved in 100 mL of DMAC, 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 mixture was cooled to room temperature, and extracted with ethyl acetate (500 mL*3) and water. The organic phases were separated, combined, dried, and concentrated. The resulting crude product was purified by column chromatography to obtain 7.3 g of the product, 4-bromo-5-nitrobenzo[d][1,3]dioxolane, in a yield of 69.4%. ESI-MS (M+H) analysis revealed that the product was 4-bromo-5-nitrobenzo[d][1,3]dioxolane. + =245.9.

[0438] Synthesis Step 4: 5-Nitro-N-((tetrahydro-2H-pyran-4-yl)methyl)benzo[d][1,3]dioxolan-4-amine (Intermediate 86-4) Intermediate 86-3 (2.5 g, 10.2 mmol) was dissolved in 35 mL of tetrahydrofuran, and (tetrahydro-2H-pyran-4-yl)methanamine (3.5 g, 30.6 mmol), BINAP (635 mg, 1.02 mmol), Pd(dba) (934 mg, 1.02 mmol), and cesium carbonate (6.6 g, 20.4 mmol) were added in that order. The mixture was refluxed at room temperature for 16 h. After completion of the reaction, the mixture was filtered through diatomaceous earth, the tetrahydrofuran was concentrated, and the mixture was extracted with ethyl acetate and water. The organic phase was separated, dried, and concentrated. The resulting 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]dioxolan-4-amine, in a 22.7% yield. ESI-MS (M+H) analysis revealed that the product was 5-nitro-N-((tetrahydro-2H-pyran-4-yl)methyl)benzo[d][1,3]dioxolan-4-amine. + =281.1.

[0439] Synthesis Step 5: 7-Bromo-5-nitro-N-((tetrahydro-2H-pyran-4-yl)methyl)benzo[d][1,3]dioxolan-4-amine (Intermediate 86-5) 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. The mixture was then allowed to react at room temperature for 4 h. After the reaction was completed, ethyl acetate (20 mL) and water were added for extraction. The organic phases were separated and combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting 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]dioxolan-4-amine. The yield was 36%, as determined by ESI-MS (M+H). + =359.0.

[0440] Synthesis Step 6: 6-Nitro-7-(((tetrahydro-2H-pyran-4-yl)methyl)amino)benzo[d][1,3]dioxolane-4-sulfonamide (Intermediate 86) Referring to the synthesis route and method of synthesis steps 4 and 5 of intermediate 70, intermediate 70-3 in synthesis step 4 is replaced with intermediate 86-5, and synthesis is carried out to obtain 80 mg of a yellow solid of intermediate 86. ESI-MS (M+H) + =360.1.

[0441] Intermediate 87: 7-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-6-nitrobenzo[d][1,3]dioxolane-4-sulfonamide JPEG0007765790000051.jpg48126 Refer to the synthetic route and method of intermediate 86, and replace (tetrahydro-2H-pyran-4-yl)methanamine in synthesis step 4 with (1r,4r)-4-(aminomethyl)-1-methylcyclohex-1-ol to obtain intermediate 87. ESI-MS (M+H) + = 388.1.

[0442] Intermediate 88: 5,8-Dibromo-6-nitro-2,3-dihydrobenzo[b][1,4]dioxine JPEG0007765790000052.jpg74163

[0443] By referring to the synthesis route and method of intermediate 86, bromochloromethane in synthesis step 3 was replaced with 1-bromo-2-chloroethane to obtain intermediate 88, which was synthesized according to ESI-MS (M+H) + = 374.1.

[0444] The following intermediate structures were obtained by synthesis with reference to the synthetic routes and methods of intermediates 86 to 88. JPEG0007765790000053.jpg209170JPEG0007765790000054.jpg58170

[0445] Intermediate 98: 7-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-6-nitrobenzo[d]oxazole-4-sulfonamide JPEG0007765790000055.jpg47123Synthesis Step 1: 7-Bromobenzo[d]oxazol-4-amine (Intermediate 98-1) Benzo[d]oxazol-4-amine (2 g, 14.92 mmol) was dissolved in 20 mL of DMF, cooled to 0 °C, and NBS (2.65 g, 14.92 mmol) was added to carry out selective bromination. After 1 h of reaction, the reaction was stopped, followed by extraction with water and ethyl acetate. The organic phase was separated, dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting crude product was purified by column chromatography to obtain 2.2 g of the product, 7-bromobenzo[d]oxazol-4-amine, in a yield of 71%. ESI-MS (M+H) analysis revealed that the product was 7-bromobenzo[d]oxazol-4-amine. + = 213.0.

[0446] Synthesis Step 2: 7-Bromobenzo[d]oxazole-4-sulfonyl chloride (Intermediate 98-2) 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, and the suspension was gradually dissolved. After reacting at 0 °C for 1 hour, 20 mL of saturated sulfur dioxide acetic acid solution was added, and the mixture was then cooled to room temperature and reacted for 2 hours. After the reaction was completed, the reaction mixture was poured into cold water, and ethyl acetate was added and extracted with stirring. The organic phase was separated, dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting crude product was purified by column chromatography to obtain 639 mg of the product, 7-bromobenzo[d]oxazole-4-sulfonyl chloride, in a 41% yield. ESI-MS (M+H) analysis revealed that the product was 7-bromobenzo[d]oxazole-4-sulfonyl chloride. + = 295.9.

[0447] Synthesis Step 3: 7-Bromo-6-nitrobenzo[d]oxazole-4-sulfonamide (Intermediate 98-3) Intermediate 98-2 (639 mg, 2.16 mmol) was added to 10 mL of concentrated sulfuric acid at 0 °C and stirred. Then, 0.2 mL of 68% concentrated nitric acid was added. The mixture was heated to 80 °C and reacted for 1 hour. The reaction mixture was then poured into 50 mL of cold aqueous ammonia and stirred for 1 hour. After the reaction was complete, the mixture was diluted with water and extracted with ethyl acetate (100 mL * 2). The organic phases were separated, combined, dried, and concentrated. The resulting crude product was purified by column chromatography to give 332 mg of the product, 7-bromo-6-nitrobenzo[d]oxazole-4-sulfonamide, in 48% yield. ESI-MS (M+H) analysis revealed the following: + = 321.9.

[0448] Synthesis Step 4: 7-(((4-Fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-6-nitrobenzo[d]oxazole-4-sulfonamide (Intermediate 98) Intermediate 98-3 (332 mg, 1.03 mmol) was dissolved in 10 mL of 1,4-dioxane solution, potassium carbonate (285 mg, 2.06 mmol), and (4-fluorotetrahydro-2H-pyran-4-yl)methanamine (179 mg, 1.34 mmol) were added in that order, and the tube was sealed and reacted at 120 °C for 9 h. After the reaction was completed, the system was cooled to room temperature, and extracted with ethyl acetate (30 mL * 2) and water. The organic phases were separated, combined, dried, and concentrated. The resulting crude product was purified by column chromatography to obtain 300 mg of solid product, intermediate 98, in a 78% yield. ESI-MS (M+H) analysis revealed that the solid product was eluted. + = 375.1.

[0449] Intermediate 99: 7-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-6-nitrobenzo[d]thiazole-4-sulfonamide JPEG0007765790000056.jpg57165

[0450] Referring to the synthesis route and method of intermediate 98, benzo[d]oxazol-4-amine in synthesis step 1 was replaced with benzo[d]thiazol-4-amine to obtain intermediate 99, which was synthesized according to ESI-MS (M+H) + =391.0.

[0451] Intermediate 100: 7-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-6-nitrobenzofuran-4-sulfonamide JPEG0007765790000057.jpg40128

[0452] Referring to the synthesis route and method of intermediate 98, benzo[d]oxazol-4-amine in synthesis step 1 was replaced with benzofuran-4-amine to obtain intermediate 100, which was synthesized according to ESI-MS (M+H) + =374.1.

[0453] Intermediate 101: (S)-7-(((1,4-dioxan-2-yl)methyl)amino)-6-nitrobenzo[d]oxazole-4-sulfonamide JPEG0007765790000058.jpg42116

[0454] Referring to the synthesis route and method of intermediate 98, (4-fluorotetrahydro-2H-pyran-4-yl)methanamine in synthesis step 4 was replaced with (S)-(1,4-dioxan-2-yl)methanamine to obtain intermediate 101. ESI-MS (M+H) + =359.1.

[0455] The following intermediate structures were obtained by synthesis with reference to the synthetic routes and methods of intermediates 98 to 101. JPEG0007765790000059.jpg171170JPEG0007765790000060.jpg255163

[0456] 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) JPEG0007765790000061.jpg50152

[0457] 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]nonan-7-yl)benzoate (001-1) Intermediate 55 (772 mg, 1.902 mmol) and Intermediate 1 (300 mg, 1.585 mmol) were dissolved in 30 mL of DCM, stirred, and STAB (1007 mg, 4.755 mmol) was slowly added. The mixture was allowed to react at room temperature for 3 h. When LCMS showed the reaction was complete, the reaction was quenched with water, and the mixture was extracted with DCM and water. The organic phases were separated, combined, and concentrated under reduced pressure. The resulting crude product was purified by column chromatography to give 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]nonan-7-yl)benzoate (587 mg), a 64% yield. ESI-MS (M+H) analysis revealed the product was 587 mg. + = 579.3.

[0458] 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) Compound 001-1 (587 mg, 1.014 mmol) was dissolved in 6 mL of THF, and 6 mL of 3N NaOH and 6 mL of MeOH were added sequentially. The reaction was allowed to proceed at room temperature for 2 h. When LCMS showed the reaction was complete, 2N HCl was added to adjust the pH to 6-7, and the mixture was concentrated to remove methanol and tetrahydrofuranol. 2-Methyltetrahydrofuranol and water were added to extract the organic phases. The organic phases were separated, combined, dried, and concentrated. The resulting crude product was slurried with MTBE, filtered, and the solid was dried at 60 °C for 3 h to obtain 418 mg of 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]nonan-7-yl)benzoic acid. The yield was 73%, as determined by ESI-MS (M+H). + = 565.3.

[0459] Synthesis 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) Add intermediate 72 (228 mg, 0.595 mmol) to reaction flask 1, add 15 mL of DCM to form a slurry, 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 of DCM, and add triethylamine (151 mg, 1.49 mmol) and stir at room temperature for 5 min. Add the reaction mixture in reaction flask 2 slowly dropwise to reaction flask 1 and continue for 1 h. After the addition is complete, continue the reaction at room temperature for 14 h. After the reaction is complete, add water and DCM to extract the mixture, separate the liquids, and concentrate the DCM phase. The resulting crude product is purified by column chromatography to obtain 385 mg of a yellow solid product of compound 001. The yield is 56%, and ESI-MS (M+H) shows the results. += 930.4.

[0460] Example 2: (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) JPEG0007765790000062.jpg45147

[0461] Referring to the synthesis route and method of Example 1, the intermediate 72 in synthesis step 3 was replaced with the intermediate 71, and the target compound 002 was synthesized. + = 975.4. 1 H NMR (400 MHz, Chloroform-d) δ 11.26 (s, 1H), 9.53 (t, J = 6.2 Hz, 1H), 9.26 (s, 1H), 8.75 (s, 1H), 8.13 (d, J = 2.6 Hz, 1H), 7.97 (s, 1H), 7.84 (d, J = 9.2 Hz, 1H), 7.66 (d, J = 2.5 Hz, 1H), 7.47 - 7.41 (m, 1H), 7.20 (s, 3H), 6.54 - 6.46 (m, 2H), 5.92 (d, J = 2.2 Hz, 1H), 4.80 (d, J = 6.3 Hz, 1H), 4.75 (d, J = 6.3 Hz, 1H), 4.66 (t, J = 6.5 Hz, 2H), 4.58 (t, J = 6.2 Hz, 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).

[0462] Example 3: 2-(3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-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) JPEG0007765790000063.jpg47149

[0463] Referring to the synthesis route and method of Example 1, the intermediate 55 in synthesis step 1 was replaced with the intermediate 61, and the target compound 085 was obtained by synthesis. + = 985.5.

[0464] 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]dioxol-4-yl)sulfonyl)benzamide (145) JPEG0007765790000064.jpg53138

[0465] Referring to the synthesis route and method of Example 1, the intermediate 1 in synthesis step 1 is replaced with the intermediate 10, and the intermediate 72 in synthesis step 3 is replaced with the intermediate 86. The target compound 145 is synthesized, and the ESI-MS (M+H) + = 1041.4. 1H NMR (400 MHz, Chloroform-d) δ 9.22 (s, 1H), 8.63 (s, 1H), 8.14 (t, J = 6.4 Hz, 2H), 7.90 (d, J = 9.1 Hz, 1H), 7.66 (d, J = 2.3 Hz, 1H), 7.43 (t, J = 2.9 Hz, 2H), 7.18 (d, J = 6.1 Hz, 2H), 7.08 (d, J = 7.4 Hz, 1H), 6.80 (d, J = 8.1 Hz, 2H), 6.52 (q, J = 3.4 Hz, 2H), 5.96 (s, 2H), 3.98 (dd, J = 11.6, 4.4 Hz, 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).

[0466] 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) JPEG0007765790000065.jpg50140

[0467] Referring to the synthesis route and method of Example 1, the intermediate 1 in synthesis step 1 is replaced with the intermediate 10, the intermediate 55 is replaced with the intermediate 56, and the intermediate 72 in synthesis step 3 is replaced with the intermediate 64, and the target compound 152 is synthesized, and the ESI-MS (M+H) + = 1033.4. 1H NMR (400 MHz, Chloroform-d) δ 9.45 (s, 1H), 8.87 (d, J = 2.3 Hz, 1H), 8.66 (t, J = 5.8 Hz, 1H), 8.14 (dd, J = 8.8, 2.4 Hz, 2H), 7.68 - 7.58 (m, 2H), 7.52 - 7.37 (m, 2H), 7.23 - 7.14 (m, 4H), 7.10 (d, J = 7.2 Hz, 1H), 6.97 (d, J = 9.3 Hz, 1H), 6.84 - 6.78 (m, 2H), 6.52 (dd, J = 3.5, 1.9Hz, 1H), 6.03 (d, J = 7.0 Hz, 1H), 3.93 - 3.83 (m, 2H), 3.77 (s, 4H), 3.74 (d, J = 2.4 Hz, 1H), 3.71 (d, J = 2.4 Hz, 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).

[0468] 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) JPEG0007765790000066.jpg75169

[0469] 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)

[0470] Referring to the synthesis route and method in Example 1, replace intermediate 55 with intermediate 56 in synthesis step 1, replace intermediate 1 with intermediate 52, and replace intermediate 72 with intermediate 64 in synthesis step 3, and synthesize to obtain 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]nonan-7-yl)-5-fluoro-N-((4-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide, ESI-MS (M+H) + = 1196.5.

[0471] Synthesis 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)

[0472] Compound 243-1 (408 mg, 0.35 mmol) was dissolved in 20 mL of DCM, 10 mL of TFA was added, and the mixture was refluxed for 18 h. After the reaction was completed, the mixture was concentrated to remove the reaction mixture, and saturated aqueous sodium bicarbonate was added to neutralize the pH to between 8 and 9. Dichloromethane was added for extraction, and the organic phase was separated and concentrated. The resulting crude product was purified by column chromatography to obtain 125 mg of solid product, compound 243, in a 34% yield. ESI-MS (M+H) analysis revealed that the product was eluted. + =1046.5.

[0473] The following target compounds were synthesized with reference to the synthetic routes and methods of Examples 1 to 6. JPEG0007765790000067.jpg246170JPEG0007765790000068.jpg250170JPEG0007765790000069.jpg255165JPEG0007765790000070.jpg248170JPEG0007765790000071.jpg244170JPEG0007765790000072.jpg255170JPEG0007765790000073.jpg242170JPEG0007765790000074.jpg248170JPEG0007765790000075.jpg238170JPEG0007765790000076.jpg255170JPEG0007765790000077.jpg252170JPEG0007765790000078.jpg253170JPEG0007765790000079.jpg255169JPEG0007765790000080.jpg253170JPEG0007765790000081.jpg243170JPEG0007765790000082.jpg243170JPEG0007765790000083.jpg255165JPEG0007765790000084.jpg245170JPEG0007765790000085.jpg237170JPEG0007765790000086.jpg237170JPEG0007765790000087.jpg255170JPEG0007765790000088.jpg243170JPEG0007765790000089.jpg244170JPEG0007765790000090.jpg255168JPEG0007765790000091.jpg255169JPEG0007765790000092.jpg250170JPEG0007765790000093.jpg255165JPEG0007765790000094.jpg244170JPEG0007765790000095.jpg255170JPEG0007765790000096.jpg255170JPEG0007765790000097.jpg246170JPEG0007765790000098.jpg244170JPEG0007765790000099.jpg243170JPEG0007765790000100.jpg255168JPEG0007765790000101.jpg255168JPEG0007765790000102.jp g255165JPEG0007765790000103.jpg225170JPEG0007765790000104.jpg231170JPEG0007765790000105.jpg23 1170JPEG0007765790000106.jpg255167JPEG0007765790000107.jpg255167JPEG0007765790000108.jpg2551 67JPEG0007765790000109.jpg248170JPEG0007765790000110.jpg255165JPEG0007765790000111.jpg220170.

[0474] Example 269 Molecular level activity test of anti-apoptotic protein BCL2 The binding ability of the anti-apoptotic protein BCL2 and the pro-apoptotic protein Bim was detected using homogeneous time-resolved fluorescence technology. The reaction was performed in a 384-well white shallow plate with a total reaction volume of 10 μL. Specifically, the reaction mixture contained 2 μL of the target compound (2% DMSO), 4 μL of His-tagged recombinant protein, and 4 μL of Biotin-tagged BIM protein. After 1 hour of incubation, 5 μL each of anti-His and streptavidin-tagged XL665 antibody diluted in detection buffer was added. The mixture was then incubated at room temperature for 4 hours, and the effect of the target compound on the binding ability of BCL2 and Bim protein was detected using an Envision multifunctional microplate reader. The Envision parameters were set to excitation at 320 nm and emission at 615 and 665 nm. The signal ratio between 665 nm and 615 nm indirectly reflected the binding ability of the anti-apoptotic protein and Bim protein. In the reaction, background wells to which no BCL2 was added and total binding activity wells containing recombinant protein and Bim protein polypeptide without any compound were set up.

[0475] IC of compounds that inhibit the binding ability of anti-apoptotic proteins to Bim protein polypeptide 50 Values ​​are calculated using Graphpad Prism 7.00 software using the formula: Y=100 / (1+10^((LogIC50-X)*HillSlope)).

[0476] Table 1. Inhibitory activity of compounds of the present invention against BCL2 JPEG0007765790000112.jpg255170JPEG0007765790000113.jpg248170

[0477] +:IC 50 <10nM; ++:10nM <IC 50 <100nM; +++:100nM <IC 50<1000nM; ++++:1000nM <IC 50 As can be seen from the results in Table 1, the compounds of the present invention have potent BCL2 inhibitory activity.

[0478] Example 270 Molecular level activity test of anti-apoptotic protein BCL2 (G101V) The binding ability of the anti-apoptotic protein BCL2(G101V) and the pro-apoptotic protein Bim was detected using homogeneous time-resolved fluorescence technology. The reaction was performed in a 384-well white shallow plate with a total reaction volume of 10 μL. Specifically, the reaction mixture contained 2 μL of the target compound (2% DMSO), 4 μL of His-tagged recombinant protein, and 4 μL of Biotin-tagged BIM protein polypeptide. After 1 hour of incubation, 5 μL each of anti-His and streptavidin-tagged XL665 antibody diluted in detection buffer was added. The mixture was then incubated at room temperature for 4 hours, and the plate was then read using the Envision multifunctional microplate reader to detect the effect of the target compound on the binding ability of BCL2(G101V) and Bim protein polypeptide. The Envision parameters were set to excitation at 320 nm, emission at 615 nm, and emission at 665 nm. The signal ratio between 665 nm and 615 nm indirectly reflects the binding ability of the anti-apoptotic protein and the Bim protein. The reaction included background wells without BCL2 and total binding activity wells containing recombinant Bim protein and no compound.

[0479] IC of compounds that inhibit the binding ability of anti-apoptotic proteins to Bim protein polypeptide 50 Values ​​are calculated using Graphpad Prism 7.00 software using the formula: Y=100 / (1+10^((LogIC50-X)*HillSlope)).

[0480] Table 2. Inhibitory activity of compounds of the present invention against BCL2 (G101V) JPEG0007765790000114.jpg218170

[0481] +:IC 50 <10nM; ++:10nM <IC 50 <100nM; +++:100nM <IC 50 <1000nM; ++++:1000nM <IC 50 As can be seen from the results in Table 2, the compounds of the present invention have potent BCL2(G101V) inhibitory activity.

[0482] Example 271 BCL2 (D103Y) molecular level activity test The binding ability of the anti-apoptotic protein BCL2(D103Y) and the pro-apoptotic protein Bim was detected using homogeneous time-resolved fluorescence technology. The reaction was performed in a 384-well white shallow plate with a total reaction volume of 10 μL. Specifically, the reaction mixture contained 2 μL of the target compound (2% DMSO), 4 μL of His-tagged recombinant protein, and 4 μL of Biotin-tagged BIM protein polypeptide. After 1 hour of incubation, 5 μL each of anti-His and streptavidin-tagged XL665 antibody diluted in detection buffer was added. The mixture was then incubated at room temperature for 4 hours. The plate was then read using the Envision multifunctional microplate reader to detect the effect of the target compound on the binding ability of BCL2(D103Y) and Bim protein polypeptide. The Envision parameters were set to excitation at 320 nm, emission at 615 nm and 665 nm. The signal ratio between 665 nm and 615 nm indirectly reflects the binding ability of the anti-apoptotic protein and the Bim protein. The reaction included background wells without BCL2 and total binding activity wells containing recombinant Bim protein and no compound.

[0483] IC of compounds that inhibit the binding ability of anti-apoptotic proteins to Bim protein polypeptide 50Values ​​are calculated using Graphpad Prism 7.00 software using the formula: Y=100 / (1+10^((LogIC50-X)*HillSlope)).

[0484] Table 3. Inhibitory activity of compounds of the present invention against BCL2 (D103Y) JPEG0007765790000115.jpg190170

[0485] +:IC 50 <10nM; ++: 10nM <IC 50 <100nM; +++:100nM <IC 50 <1000nM; ++++:1000nM <IC 50 As can be seen from the results in Table 3, the compounds of the present invention have potent BCL2(D103Y) inhibitory activity.

[0486] Example 272 Tumor growth inhibitory activity test The cell proliferation inhibitory ability of compounds against RS4;11 was tested using the MTS assay. MTS is a tetrazolium compound that is reduced to a colored formazan product by various dehydrogenases in the mitochondria of viable cells. The color intensity correlates highly with the viable cell count of specific sensitive cell lines within a certain range. RS4;11, RS4;11(BCL-2-G101V), and MOLT-4 tumor cells were cultured and harvested. 180 μL of cell suspension was added to each well of a 96-well cell plate. 20 μL of DMSO (0.2% DMSO) was added to the control cell wells. 20 μL of gradiently diluted compounds were added to the cell wells. The treated cells were then incubated in an incubator at 37°C and 5% CO2 for 3 days. After incubation, the reaction mixture was prepared according to the MTS reagent kit, and 20 μL was added to each well. The mixture was then incubated at 37°C and 5% CO2 for 3-4 hours. The absorbance value at 490 nm was read from the microplate, and the absorbance value at 690 nm was used as the background value. 490 nm~OD 690nm is the final original data. The formula for calculating the inhibition rate of a compound is as follows: Inhibition rate = (OD DMSO -OD Compound ) / (OD DMSO -OD blank )×100%.

[0487] Growth inhibition IC of compounds 50 is obtained by fitting with GraphPad Prism software and calculated by the formula: Y=100 / (1+10^((LogIC50-X)*HillSlope)).

[0488] Table 4. Growth inhibitory activity of compounds of the present invention against RS4;11 JPEG0007765790000116.jpg183170

[0489] +:IC 50 <0.5nM; ++:0.5nM <IC 50 <1nM; +++:1nM <IC 50 <100nM; ++++:100nM <IC 50 As can be seen from the results in Table 4, the compounds of the present invention have significant growth inhibitory activity against RS4;11 cells.

[0490] Example 273 Test plan for BCL-XL enzyme molecular level activity test and platelet viability detection

[0491] (1) BCL-XL enzyme molecular level activity test The reaction was performed in a 384-well white shallow plate, with a total reaction volume of 10 μL. Specifically, the reaction mixture contained 2 μL of the target compound (2% DMSO), 4 μL of His-tagged recombinant protein, and 4 μL of Biotin-tagged BIM protein polypeptide. After 1 hour of incubation, 5 μL each of anti-His and streptavidin-tagged XL665 antibody dilutions diluted in detection buffer was added. The mixture was then incubated at room temperature for 4 hours, and the assay was then read using an Envision multifunction microplate reader to determine the effect of the target compound on the binding ability of BCL-XL and Bim protein polypeptide. The Envision parameters were set to excitation at 320 nm and emission at 615 and 665 nm. The signal ratio between 665 and 615 nm indirectly reflects the binding ability of the anti-apoptotic protein and Bim protein polypeptide. A background well without BCL2 and a total binding activity well containing recombinant protein and Bim protein polypeptide without compound were set up in the reaction.

[0492] IC of compounds that inhibit the binding ability of anti-apoptotic proteins to Bim protein polypeptide 50 Values ​​are calculated using Graphpad Prism 7.00 software using the formula: Y=100 / (1+10^((LogIC50-X)*HillSlope)).

[0493] (2) Platelet viability detection test Add 10 mL of platelet-rich plasma to 30 mL of ACD-A solution, mix thoroughly, then centrifuge at 1200 g and discard the supernatant. Add 10 mL of ACD-A solution, resuspend, mix thoroughly, and centrifuge at 1200 g for 10 min and discard the supernatant. Add 5 mL of HEPES-Tyrode's buffer containing 1 μM PGE1 and 0.2 U / mL apyrase, invert gently, and centrifuge at 800 g for 5 min and discard the supernatant. Add 10 mL of HEPES-Tyrode's buffer containing 1 μM PGE1 and 0.2 U / mL apyrase, resuspend, and centrifuge at 1000 g for 5 min and discard the supernatant. Add 2 mL of HEPES-Tyrode's buffer + 10% FBS containing 1 μM PGE1 to resuspend the platelets. Transfer 200 μL to a centrifuge tube and dilute to 2 mL. The compound was then diluted 1:1, 0.8, 0.6, 0.4, 0.2, 0.1, 0.08, 0.06, 0.04, 0.02, and 0.01, refilled to 100 μL, and 50 μL of CTG reagent was added to detect cell viability. The highest dilution ratio was selected so that the fluorescence value did not exceed 108, and 90 μL was added per well to a 96-well cell plate for chemiluminescence measurement. The compound was prepared in HEPES-Tyrode's buffer + 10% FBS containing 1 μM PGE1, added to the cells, and gently tapped to homogenize. After 24 h, 50 μL of CTG was added to detect cell viability.

[0494] IC of compounds inhibiting platelet viability 50 The value is calculated using Graphpad Prism 7.00 software using the formula: Y=100 / (1+10^((LogIC50-X)*HillSlope)).

[0495] Table 5. Inhibitory activity of compounds of the present invention against BCL-XL JPEG0007765790000117.jpg154170

[0496] Table 6. Results of compounds of the present invention on human platelet viability JPEG0007765790000118.jpg135142

[0497] Note: Compound a is selected from WO2021208963 JPEG0007765790000119.jpg53141

[0498] As can be seen from the results in Tables 5 and 6, the compounds of the present invention have no inhibitory activity against BCL-XL and no toxic effect on human platelets.

[0499] Example 274 CYP3A4 enzyme inhibitory activity The inhibitory activity of compounds against human CYP3A4 enzymes is detected using the VIVID® CYP3A4 GREEN SCRNING KIT reagent kit. The Vivid® CYP450 Screening Reagent Kit contains Vivid® Substrate, Vivid® Fluorescent Standard, Reaction Buffer, Vivid® Regeneration System, NADP+, and CYP450 BACULOSOMES® Plus Reagent. The kit is operated according to the manufacturer's instructions, and a blank control group without the addition of any compound is set up at the same time.

[0500] IC of compounds inhibiting human CYP3A4 enzyme 50 The value is calculated using Graphpad Prism 7.00 software using the formula: Y=100 / (1+10^((LogIC50-X)*HillSlope)).

[0501] Table 7. Results of CYP3A4 enzyme inhibitory activity of compounds of the present invention JPEG0007765790000120.jpg96170As can be seen from the results in Table 7, the compounds of the present invention have no inhibitory effect on the CYP3A4 enzyme.

[0502] Example 275 Absorption test in rats Experimental method: SD rats were used as experimental animals and 10 mg / kg was administered intragastrically. Blood was collected at 0, 0.5, 1, 2, 3, 4, 6, 8, and 24 hours after intragastric administration. 3 mL of whole blood was collected, centrifuged, and 1 mL of plasma was collected and analyzed by LC-MS.

[0503] Table 8. Results of rat absorption test of the compound of the present invention JPEG0007765790000121.jpg45170Note: Compound b is selected from compound number 142 of CN114478520A.

[0504] As can be seen from the results in Table 8, the compounds of the present invention have good pharmacokinetic properties in SD rats, which supports the oral administration route.

[0505] Example 276 Dog absorption test Experimental method: Beagle dogs were used as experimental animals, and 5 mg / kg was administered intragastrically. Blood was collected at 0, 0.5, 1, 2, 3, 4, 6, 8, and 24 hours after intragastric administration. 3 mL of whole blood was collected, centrifuged, and plasma was extracted and analyzed by LC-MS.

[0506] Table 9. Results of dog absorption test of the compound of the present invention JPEG0007765790000122.jpg31170Note: DNAUC is AUC(h*ng / mL) / dose(mg / kg).

[0507] As can be seen from the results in Table 9, the compounds of the present invention have good pharmacokinetic properties in beagle dogs, which supports the oral administration route.

[0508] Example 277 In vivo antitumor effect RS4;11 cells were subcutaneously inoculated into NOD / SCID mice to create tumor models. 3 When the mice reached a growth stage, they were divided into groups and administered the following treatments: the control group received intragastric administration of a corresponding volume of CMC-Na solution, and the test group received intragastric administration of 5 mg / kg of the test compound. The mice were weighed twice a week to determine changes in body weight and tumor size, and after 8 days, the effects of the compound on the tumors transplanted into RS4;11 mice were evaluated.

[0509] Relative tumor growth rate T / C%=T RTV / C RTV× 100% (TRTV: mean RTV of treatment group, C RTV RTV is calculated based on the tumor measurement results, and the formula is RTV = V t / V0, where V0 is the tumor volume measured at the time of administration (i.e., D0), Vt is the tumor volume at a given measurement, and T RTV and C RTV data is taken on the same day.

[0510] Table 10. In vivo antitumor activity of compounds of the present invention JPEG0007765790000123.jpg46170Note: Compound b is selected from compound number 142 of CN114478520A.

[0511] As can be seen from the results in Table 10, the compounds of the present invention have a significant tumor-suppressing effect, and no abnormalities were observed in the animals during the test period.

Claims

1. It has the structure shown in the following general formula (I): or a stereoisomer thereof, a mixture of stereoisomers thereof, or a pharmaceutically acceptable salt thereof; *The C in the notation is in the R or S configuration. Ring A is selected from absent, a 5-membered heterocyclyl group, a 6-membered heterocyclyl group, a 5-membered heteroaryl ring, and a 6-membered heteroaryl ring, wherein the heterocyclyl group and the heteroaryl ring contain 1 to 4 heteroatoms selected from N, O, and S; R ２ is selected from hydrogen, methyl, halogen, hydroxy, amino, oxo, cyano, and nitro groups; Y １ , Y ２ , Y ３ are each independently, CR ７ , N; R ７ is selected from H, halogen, L ２ is a chemical bond, -NR ａ -, -O-, L ３ is -C(O)NR ８ SO ２ - is selected from, R ８ is H, C １ -C ８ alkyl groups, R ３ teeth, is selected from R １０ is selected from hydrogen, deuterium, halogen, nitro group, oxo group, and cyano group; R １０ may be substituted on a carbon atom or a nitrogen atom, Ring B is selected from 5-12 membered spiroheterocyclyl groups; Ring C is a benzene ring; X is CH ２ , N.R. ｂ is selected from R b is is selected from o is selected from 0, 1, 2, 3, and 4; p is selected from 0, 1, 2, and 3; q is selected from 0, 1, 2, and 3; r is selected from 0, 1, 2, and 3; s is selected from 0, 1, 2, and 3; t is selected from 0, 1, 2, and 3; R ａ is H, R ４ is H, halogen, C １ -C ８ Alkyl group, halogenated C １ -C ８ alkyl groups, R ５ is H or methyl, R ６ is H, deuterium, halogen, C １ -C ８ alkyl groups, L １ is a chemical bond, NR ｆ , O; R ｆ is H, C １ -C ８ alkyl groups, R １ teeth wherein any carbon atom on the ring is substituted with one or more N or O; y is selected from 0, 1, 2, 3, and 4; v is selected from 0, 1, 2, and 3; R ｍ is hydrogen, deuterium, C １ -C ８ Alkyl group, halogen, cyano group, amino group, nitro group, hydroxy group, oxo, alkoxy group, C １ -C ８ and the alkyl, cycloalkyl and heterocyclyl groups are selected from the group consisting of alkoxy, halogenated C 1 -C 8 alkyl, C 1 -C 8 alkylcarbonyl, C 1 -C 8 alkylamino, halogenated C 1 -C 8 alkylamino, C 3 -C 12 cycloalkyl and 3-12 membered heterocyclyl groups, wherein the alkyl, cycloalkyl and heterocyclyl groups further comprise one or more R ｒ may be substituted with R ｒ is hydrogen, deuterium, C １ -C ８ selected from alkyl groups, halogens, cyano groups, amino groups, hydroxy groups, oxo, C 1 -C 8 alkylamino groups, halogenated C 1 -C 8 alkylamino groups, halogenated C 1 -C 8 alkyl, nitro groups, carboxy groups, and amide groups; When Ring A is selected from absent, X is NR ｂ and Y １ / Y ２ / Y ３ At least one of is N or CR ７ and R ７ is not H.

2. It has a structure represented by general formula (I'), or a stereoisomer thereof, a mixture of stereoisomers thereof, or a pharmaceutically acceptable salt thereof; *The C in the notation is in the R or S configuration. Ring A is absent, a 6-membered heterocycle, a 6-membered heteroaryl ring; Z is selected from N, CH; R ２ is selected from hydrogen, a methyl group, and a halogen; Y １ , Y ２ , Y ３ are each independently, CR ７ , N; R ７ is selected from H, halogen, Ring A is selected from absent and Y １ , Y ２ , Y ３ If two of the are CH, Another Y １ / Y ２ / Y ３ is N or CR ７ and R ７ is not H, R ３ teeth is selected from R １０ is selected from hydrogen and halogen, R １０ may be substituted on a carbon atom or a nitrogen atom, Ring B is is selected from o is selected from 0, 1, 2, 3, and 4; p is selected from 0, 1, 2, and 3; q is selected from 0, 1, 2, and 3; r is selected from 0, 1, 2, and 3; s is selected from 0, 1, 2, and 3; L ２ is a chemical bond, NR ａ , O; X is CH2, NR ｂ is selected from R ｂ teeth, is selected from R ａ is H, R ４ is H, halogen, C １ -C ８ Alkyl group, halogenated C １ -C ８ alkyl groups, R ５ is H or a methyl group, R ６ is H, deuterium, halogen, C １ -C ８ alkyl groups, Ring C is a benzene ring; L １ is NR ｆ , O; R ｆ is H, C １ -C ８ alkyl groups, R １ teeth wherein any carbon atom on the ring is substituted with one or more N or O; y is selected from 0, 1, 2, 3, and 4; v is selected from 0, 1, 2, and 3; R ｍ is hydrogen, deuterium, C １ -C ８ and the alkyl group, the cycloalkyl group, and the heterocyclyl group are selected from the group consisting of alkyl groups, halogens, cyano groups, amino groups, nitro groups, hydroxy groups, oxo groups, C 1 -C 8 alkoxy groups, halogenated C 1 -C 8 alkyl groups, C 1 -C 8 alkylcarbonyl groups, C 1 -C 8 alkylamino groups, halogenated C 1 -C 8 alkylamino groups, C 3 -C 12 cycloalkyl groups, and 3- to 12-membered heterocyclyl groups, and the alkyl groups, cycloalkyl groups, and heterocyclyl groups may further comprise one or more R ｒ may be substituted with R ｒ is hydrogen, deuterium, C １ -C ８ 2. The compound according to claim 1, characterized in that it is selected from the group consisting of alkyl groups, halogens, cyano groups, amino groups, hydroxy groups, oxo, C 1 -C 8 alkylamino groups, halogenated C 1 -C 8 alkylamino groups, halogenated C 1 -C 8 alkyl groups, nitro groups, carboxy groups, and amides.

3. It has a structure shown in general formula IIa or IIb, 3. The compound according to claim 2, characterized in that it is a stereoisomer thereof, a mixture of stereoisomers thereof or a pharmaceutically acceptable salt thereof.

4. having a structure shown in general formula IIIa or IIIb, 4. The compound according to claim 3, characterized in that it is a stereoisomer thereof, a mixture of stereoisomers thereof or a pharmaceutically acceptable salt thereof.

5. Ring A is Non-existent, or 2. The compound according to claim 1, characterized in that it is selected from:

6. having a structure shown in general formula IVa, IVb, or IVc, or a stereoisomer thereof, a mixture of stereoisomers thereof, or a pharmaceutically acceptable salt thereof; R ２ is hydrogen, methyl, or halogen, and R ２ The compound according to claim 4, wherein: may be substituted on a carbon atom or a nitrogen atom.

7. It has a structure shown in general formulas Va to Vf, or a stereoisomer thereof, a mixture of stereoisomers thereof, or a pharmaceutically acceptable salt thereof; R １０ is hydrogen or a halogen, R ２ is hydrogen, methyl, or halogen, and R ２ The compound according to claim 6, wherein: may be substituted on a carbon atom or a nitrogen atom.

8. It has a structure shown in general formula VIa or VIb, or a stereoisomer thereof, a mixture of stereoisomers thereof, or a pharmaceutically acceptable salt thereof; Y １ , Y ２ , Y ３ When two of the groups are CH, the other Y １ / Y ２ / Y ３ is N or CR ７ and R ７ is a halogen, R １ teeth wherein any carbon atom on the ring is substituted with one or more N or O; y is selected from 0, 1, 2, 3, and 4; 5. The compound according to claim 4, wherein v is selected from 0, 1, 2, and 3.

9. The -L 1 -R 1 fragment is Selected from: The compound according to claim 1, characterized in that

10. Ring A is selected from a 5-membered heterocycle and a 5-membered heteroaryl group; ３ is -C(O)NHSO ２ - is selected from, Ring C is a benzene ring, and ring B is and nitrogen is selected from Y １ / Y ２ / Y ３ The compound of claim 1, wherein the compound is attached to a ring comprising:

11. X is CR ｂ R ｃ is selected from R ｂ , R ｃ are each independently H; o is selected from 0, 1, and 2; L ２ The compound according to claim 10, characterized in that is selected from a chemical bond, -NH-, and -O-.

12. having the structure of general formula (VII): or a stereoisomer thereof, a mixture of stereoisomers thereof, or a pharmaceutically acceptable salt thereof; Y １ , Y ２ , Y ３ are each independently, CR ７ , N; R ７ 11. The compound according to claim 10, characterized in that is selected from H, halogen.

13. is selected from R 6 is isopropyl; 2. The compound of claim 1, wherein Y2 is N or CF.

14. The following compounds:

2. The compound according to claim 1, characterized in that it is selected from: or a stereoisomer thereof, or a stereoisomeric mixture thereof, or a pharmaceutically acceptable salt thereof.

15. A pharmaceutical composition comprising one or more compounds according to any one of claims 1 to 14.

16. 15. Use of a compound according to any one of claims 1 to 14 in the manufacture of a medicament, alone or in combination with other drugs, for the treatment of a disease, disorder or condition that would benefit from the inhibition of BCL-2 activity.

17. The other drugs include alkylating agents, angiogenesis inhibitors, antibodies, antimetabolites, antimitotics, antiproliferative agents, antivirals, aurora kinase inhibitors, other apoptosis promoter inhibitors, death receptor pathway activators, Bcr-Abl kinase inhibitors, bispecific T cell engager antibodies, antibody drug conjugates, biological response modifiers, cyclin-dependent kinase inhibitors, cell cycle inhibitors, cyclooxygenase-2 inhibitors, DVDs, leukemia viral oncogene homolog 2 receptor inhibitors, growth factor inhibitors, heat shock protein inhibitors, histone deacetylase inhibitors, hormone therapy, immunologic agents, inhibitors of apoptosis proteins, intercalating antibiotics, kinase inhibitors, kinesin inhibitors, Jak2 inhibitors, mammalian target of rapamycin inhibitors, microRNAs, mitogen-activated extracellular signal-regulated kinase inhibitors, multivalent binding proteins, nonsteroidal anti-inflammatory drugs, poly(ADP) 17. The use according to claim 16, characterized in that the inhibitor is selected from the group consisting of (adenosine diphosphate)-ribose polymerase inhibitors, chemotherapy platinum agents, polo-like kinase inhibitors, phosphatidylinositol 3-kinase inhibitors, BTK inhibitors, immune checkpoint inhibitors, proteasome inhibitors, purine analogues, pyrimidine analogues, receptor tyrosine kinase inhibitors, retinoids / deltoid plant alkaloids, small interfering RNAs, topoisomerase inhibitors, ubiquitin ligase inhibitors and analogues.

18. 17. The use according to claim 16, characterized in that the disease, disorder or condition is selected from an infectious disease, an immune disease, an inflammatory disease or a cell proliferative disease.

19. the disease is a hematological disease and / or a solid cancer, the hematological disorder 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; 19. The use according to claim 18, characterized in that the solid cancer is one or more of osteosarcoma, skin cancer, breast cancer, renal 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 hyperplasia, melanoma.

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